Topical Ocular Delivery Methods and Devices for Use in the Same

ABSTRACT

Methods of administering a liquid formulation of an ophthalmic agent to a topical ocular location of an eye are provided. Aspects of the methods include delivering to the topical ocular location a dose of the liquid formulation that can be wholly accommodated by the tear film of the eye. Devices and kits for practicing the methods are also provided. The methods, compositions and kits find use in a variety of applications, including therapeutic, diagnostic and cosmetic applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT Application Ser. No.US2019/027018 filed Apr. 11, 2019, which application, pursuant to 35U.S.C. § 119(e), claims priority to the filing date of U.S. ProvisionalPatent Application Ser. No. 62/656,552 filed Apr. 12, 2018, and U.S.Provisional Patent Application Ser. No. 62/814,764 filed Mar. 6, 2019;the disclosures of which applications are herein incorporated byreference.

INTRODUCTION

There are many situations in which it is desirable to administer aliquid formulation to an ocular surface, e.g., for the treatment of anocular condition, such as a disease condition, for the alleviation ofdiscomfort, e.g., dry eye, for the improvement of appearance, e.g.,bloodshot eye, and for diagnostic purposes. The administration of liquidformulations onto an ocular surface generally is accomplished bydepositing one or more drops of the liquid formulation from a smallcontainer or bottle (e.g., a conventional eye dropper) directly onto theocular surface. In such instances, the drops of the liquid formulationare either self-administered or administered by another, such as ahealth care provider or caregiver.

A conventional eye dropper dispenses single drops that are about 30-50μl in volume. However, since the human eye can typically retain onlyabout 7 μl of fluid on the corneal surface, larger deposited volumesresult in overflow and loss of most of the medication from the eyesurface. In addition, a large volume of a single drop, such as 30 or 50μl, causes a blinking reflex, which removes the majority of the fluidfrom the ocular surface, and also causes discomfort and reflex tearing.

These factors can make administration of eye drops from conventional eyedroppers (whether self-administered or administered by another)problematic. For example, with conventional eye droppers it is notpossible to administer a precise, known dose of a liquid formulation andactive agent to the eye. Furthermore, there is substantial waste thatoccurs using conventional eye droppers. In addition, administration byconventional eye dropper can result in patient discomfort.

SUMMARY

Embodiments of the invention address the need in the art for improvedadministration of liquid formulations to the ocular surface.Improvements realized by embodiments of the invention include, but arenot limited to: the ability to administer a precise, known dose of aliquid formulation and active agent to the eye; the elimination ofliquid formulation waste and the reduction, if not elimination, ofpatient discomfort during ocular administration.

Methods of administering a liquid formulation of an ophthalmic agent toa topical ocular location of an eye are provided. Aspects of the methodsinclude delivering to the topical ocular location a dose of the liquidformulation that can be wholly accommodated by the tear film of the eye.Devices and kits for practicing the methods are also provided. Themethods, compositions and kits find use in a variety of applications,including therapeutic, diagnostic and cosmetic applications.

BRIEF DESCRIPTION OF THE FIGURES

Having thus summarized the general nature of the invention and some ofits features and advantages, certain embodiments and modificationsthereof will become apparent to those skilled in the art from thedetailed description herein having reference to the figures that follow,of which:

FIG. 100 illustrates a perspective view of an embodiment of theinvention.

FIG. 200 illustrates a side view of the embodiment of FIG. 100, as wellas the electronic circuit thereof.

FIG. 300A illustrates an exploded view of the embodiment of FIG. 100 andFIG. 200 showing the ampule and the magnetic transducer separately. FIG.300B, FIG. 300C and FIG. 300D illustrate various views of such a devicethat includes a cover to seal the orifice and allow for use of apreservative free liquid formulation.

FIG. 400A and FIG. 400B provide views of an internal mechanism of ahandheld device that includes a piezoelectric actuator according to anembodiment of the invention;

FIG. 500A illustrates an alignment system which facilitates aligning thefluid delivery assembly relative to the eye of the user when a reflectedimage of the eye appears in focus to the user. FIG. 500B, FIG. 500C andFIG. 500D illustrate variations where the fluid is emitted off-axis orat an angle relative to a central visual axis of the iris. FIG. 500Eillustrates another variation of the optical alignment system.

FIG. 600A, FIG. 600B and FIG. 600C illustrate side and front views ofthe assembly when the eye of the user is properly positioned relative tothe assembly for fluid delivery.

FIG. 600C illustrates a front view of the assembly where the radius ofcurvature of the mirror is relatively smaller than in FIG. 600B suchthat the image of an eye in reflection appears at higher magnificationthan in FIG. 600B.

FIG. 700A and FIG. 700B illustrate front and side views of an embodimentof the assembly having a protective covering feature.

FIG. 800 illustrates another embodiment of a fluid delivery devicehaving a ring LED around a concave mirror and an IR distance sensor.

FIGS. 900A to 1400 provide further details regarding results obtainedduring experiments as described in the Experimental section, below.

DETAILED DESCRIPTION

Methods of administering a liquid formulation of an ophthalmic agent toa topical ocular location of an eye are provided. Aspects of the methodsinclude delivering to the topical ocular location a dose of the liquidformulation that can be wholly accommodated by the tear film of the eye.Devices and kits for practicing the methods are also provided. Themethods, compositions and kits find use in a variety of applications,including therapeutic, diagnostic and cosmetic applications.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

While the apparatus and method has or will be described for the sake ofgrammatical fluidity with functional explanations, it is to be expresslyunderstood that the claims, unless expressly formulated under 35 U.S.C.§ 112, are not to be construed as necessarily limited in any way by theconstruction of “means” or “steps” limitations, but are to be accordedthe full scope of the meaning and equivalents of the definition providedby the claims under the judicial doctrine of equivalents, and in thecase where the claims are expressly formulated under 35 U.S.C. § 112 areto be accorded full statutory equivalents under 35 U.S.C. § 112.

Methods

As summarized above, aspects of the present disclosure include methodsof administering a liquid formulation of an ophthalmic agent to atopical ocular location of an eye of a subject. By topical ocularlocation is meant a region (i.e., area or domain) of an external surfaceof an eye, such as a region of a cornea, a region of a conjunctiva, aregion that includes both corneal and conjunctival components, etc. Insome instances, the topical ocular location is an area or region that isoffset relative to the optical axis of the eye. In some instances, thetopical ocular location is on either the bulbar or tarsal conjunctiva,or in the conjunctival fornix. In other words, the topical ocularlocation is one that is displaced from the center of the pupil or thecenter of the iris. While the magnitude of the distance of theoffset/displacement may vary, in some instances the magnitude rangesfrom 1 to 30 mm, such as 2 to 20 mm, e.g., 5 to 15 mm, including 5 to 10mm. While the target topical ocular location may vary in size, in someinstances the size of the target topical ocular region ranges from 2.5to 12, such as 3 to 9 mm².

Aspects of the invention include delivering a dose or volume of theliquid formulation of the ophthalmic agent that can be whollyaccommodated by the tear film of the topical ocular location. The tearfilm of the ocular location is the film that is associated with thetopical ocular location. As such, the tear film is the film or layer oftear liquid that is present on the eye surface on which the topicalocular location, e.g., as described above, is located. As the deliveredvolume of the liquid formulation is a volume that can be whollyaccommodated by the tear film of the topical ocular location, it mayalso be a volume that may be wholly accommodated by the ocular surfacethat includes the topical ocular location. By “wholly accommodated bythe ocular surface” is meant that, upon delivery, the delivered volumeis a volume that can be held on the surface of the eye to which it isadministered without any excess liquid running off of the surface of theeye and over the eyelid, e.g., in the form of tears. While the volume ofa given delivered volume may vary, in some instances the volume rangesfrom 1 to 15 μl, such as 3 to 10 μl, including 5 to 10 μl. In someinstances, the volume of liquid formulation that is administered to theocular surface does not result in a blinking reflex. As such, deliveryof a volume of liquid in accordance with embodiments of the inventiondoes not result in reflex tearing, blepharospasm/blinking, which inembodiments allows for a precise, known amount of active agent to bedelivered to the topical location.

An advantage of embodiments of the invention is that because the volumeof liquid formulation that is precisely administered to the ocularsurface can be wholly accommodated on the ocular surface, exact, knownamounts of an ophthalmic agent are delivered to the topical ocularlocation. As reviewed above, volumes of a liquid formulation aredelivered in a manner that minimizes, if not eliminates, reflex tearingand volumetric losses of the liquid formulation. As such, in a givenliquid formulation administration, the administered fluid aliquot isexactly what is retained on the ocular surface. Accordingly, methods ofthe invention allow for delivery of exact known mass amounts of a givenophthalmic agent. In other words, a precise amount of ophthalmic agentis delivered to the ocular surface, in contrast to other administrationprotocols where a precise, known amount cannot be delivered, predictedor measured because of one or more of loss through reflex blinking ortearing, loss through failure of entire dose to reach ocular surface(e.g., as occurs in delivery of mists or aerosols), etc. In methods ofthe invention, the amount (mass) of the ophthalmic agent delivered tothe ocular surface is a mass equal to the administered volume times theconcentration of ophthalmic agent in the administered liquidformulation. For example, if a given administered volume is 10microliters of a 1% ophthalmic agent (10 mg/mL) solution, then the knownmass of ophthalmic agent delivered to the ocular surface is 0.1 mg.Similarly, when delivering 4 microliters of a 2% ophthalmic agent (20mg/mL) solution in accordance with the invention, the known mass ofophthalmic agent delivered to the ocular surface is 0.08 mg. Thisability to know the mass of ophthalmic agent delivered to a topicalocular surface represents a distinct advantage as compared to othermethods of delivering active agents to topical ocular locations, e.g.,using conventional eye drop protocols or aerosol/mist delivery devices.For example, with a conventional eye drop with a volume of 40microliters, it is unknown exactly how much of the active agent or drugis actually delivered and maintained on the ocular surface, because (1)the ocular surface cannot hold 40 microliters on its surface, (2) alarge portion of the eye drop spills over the lid margin and is wipedwith a tissue, and (3) additional drop volume is lost through thelacrimal system, and (4) reflex tearing ensues as a result of the largedrop volume and leads to dilution of the drug concentration. Withrespect to devices that deliver a formulation in mist/aerosol format,not all of the dispensed formulation can be ensured to have landed onthe cornea or ocular surface, and not the surrounding periocularsurfaces.

While the mass of given ophthalmic agent delivered to a topical ocularlocation in accordance with embodiments of the invention may varydepending on a number of considerations, including the nature of theagent, the condition to be treated, the age of the subject, etc., insome instances the delivered mass ranges from 0.00001 mg to 10 mg, suchas 0.00005 mg to 5 mg, including 0.01 to 1 mg, such as 0.05 to 0.5 mg,including 0.75 to 0.15 mg.

Aspects of the invention include delivering a micro-dose of anophthalmic agent to a topical ocular location. In some instances, thedelivered micro-dose is one that has an efficacy comparable to areference dosage having a volume that exceeds the capacity of the tearfilm of the target topical ocular location. The reference dosage in suchinstances, apart from volume, is otherwise identical to that of thedelivered dosage. As such, the concentration of the active agent in thereference dosage is the same as the concentration of the active agent inthe delivered dosage. The volume of the reference dosage exceeds that ofthe delivered dosage, e.g., by 2-fold or greater, such as 3-fold orgreater. In some instances, the reference dosage has a volume rangingfrom 25 to 60 μl, such as 30 to 50 μl. In some instances, the referencedosage is a dosage that is delivered by a standard eye dropper device.

Micro-doses of embodiments of the invention are effective, e.g., totreat an ocular condition for which they are administered, with at leastreduced adverse effects, and in some instances without substantialadverse effects, e.g., adverse effects that might otherwise require anadditional medicinal agent to counteract the adverse effects and/orresult in reduced patient compliance. As such, the magnitude of anyadverse effects caused by administration of the micro-doses is reducedand in some instances sufficiently minimal such that no intervention isnecessary to ameliorate the adverse effects, e.g., administration of anadditional active agent that ameliorates the adverse effects. In someinstances, the subject experiences no adverse effects followingadministration of a micro-dose. As the micro-doses of embodiments of theinvention are effective to treat an ocular condition for which they areadministered without substantial adverse effects, in some instances theophthalmic agent is the only active agent present in the micro-dose,such that the micro-dose includes no other active agents, includingagents that ameliorate any adverse effects of the ophthalmic agent thattreats condition for which it is being administered. For example, wherepilocarpine is administered in a micro-dose in accordance withembodiments of the invention, the micro-dose may not include any agentsthat ameliorate adverse effects of pilocarpine, where such agentsinclude vasoconstrictors, such as oxymetazoline, naphazoline,tetrahydrozoline, and alpha agonists (e.g. brimonidine) and the like.

The ability to deliver precise known amounts in accordance with theinvention allows for the delivery of the same dosage or amount of anactive agent using a variety of different regimens (the term “regimen”is used its conventional sense to refer to the schedule of doses of anactive agent, including the time between doses, the duration oftreatment and the amount to be administered each time), where for agiven subject a single regimen may be repeatedly used or a number ofdifferent regimens may be employed over a given course of treatment. Assuch, the methods and devices described herein provide for the samedosage of active agent to be delivered by multiple different regimens.For example, with respect to first micro-dose in which a given volume ofa drug formulation having a given active agent concentration isadministered, the volume of drug formulation and concentration of activeagent in the formulation may be varied to obtain a micro-dose thatadministers the same dosage but by a different regimen. For example, ascompared to a first micro-dose, the volume of an active agentformulation that is delivered may be increased and the concentration ofactive agent in the delivered fluid decreased to the extent that thetolerability and efficacy of the second regimen is superior to that ofthe first regimen even though the precise dose of active agentadministered as determined by weight in micrograms, milligrams or gramsof the API is identical amongst the first and second regimens.

As summarized above, methods of the invention deliver a volume of aliquid formulation of an ophthalmic agent, i.e., dose, to an ocularsurface. The terms “agent,” “compound,” and “drug” are usedinterchangeably herein to refer to a molecule or molecular combinationthat has a physiological effect upon contact with a subject viaadministration to a topical ocular location of the subject. The activeagent may include one or more functional groups that provide forstructural interaction with the intended target. Functional groups ofinterest include, but are not limited to: groups that participate inhydrogen bonding, hydrophobic-hydrophobic interactions, electrostaticinteractions. Specific groups of interest include, but are not limitedto amines, amides, sulfhydryls, carbonyls, hydroxyls, carboxyls, etc.Active agents of interest may include cyclical carbon or heterocyclicstructures and/or aromatic or polyaromatic structures substituted withone or more of the above functional groups. Also of interest as moietiesof active agents are structures found among biomolecules, includingpeptides/proteins, saccharides, fatty acids, steroids, purines,pyrimidines, nucleic acids, derivatives, structural analogs orcombinations thereof. Active agents of interest include small, mediumand large molecule active agents. Small molecule active agents are thoseactive agents having a molecular weight ranging from 18 to 2500 daltons,such as 1000 to 1500 daltons and including 250 to 1000 daltons. Mediummolecule active agents are those active agents having a molecular weightranging from 2500 to 10,000 daltons, such as 4,000 to 8,000 daltons andincluding 5000 to 7000 daltons. Large molecule active agents are thoseactive agents having a molecular weight of 10,000 daltons or more, suchas 100,000 daltons or more, where in certain instances these largemolecule active agents range from 1 million to 30 million daltons, suchas 5 million to 20 million daltons and including 10 million to 15million daltons. Examples of active agents that may present in theliquid formulation include, but are not limited to: anti-microbialagents (including but not limited to antibiotics (e.g., Sulfacetamide,Trimethoprim, Ofloxacin, Gentamicin, Neomycin, Tobramycin, Polymyxin,Ciprofloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin), antivirals,anti-fungals (e.g., Polyenes, such as Amphotericin B (AMB)-polyenemacrolide antibiotic and Natamycin, and Azoles, such as Miconazol,Ketoconazole, Itraconazole, Flucanazole, Voriconazole, Posaconazole andEchinocandins), anti-inflammatories (including but not limited tosteroids (e.g., Corticosteroids, such as Prednisolone, Prednisolon,Dexamethasone, Loteprednol, Difluprednate, Fluorometholone, Rimexoloneand Medrysone) and non-steroidal anti-inflammatory drugs (NSAIDS, suchas Ketorolac), etc.), anti-allergy agents (including but not limited toanti-histamines (e.g., Azelastine hydrochloride, Emedastine difumarateand Levocabastine) and mast cell stabilizers, etc.), vasoconstrictors,anesthetics (e.g., Lidocaine, Tetracaine Proparacaine), analgesics,intraocular pressure lowering agents (including but not limited toprostaglandin analogs (e.g., Bimatoprost, Iatanoprost, Travoprost andTafluprost,), ROK inhibitors (e.g., Netarsudil), beta blockers (e.g.,Levobunolol, Timolol, Betaxolol, Carteolol and Metipranolol), carbonicanhydrase inhibitors (e.g., Brinzolamide, Methazolamide and Dorzolamide)and alpha agonists (e.g., Apraclonidine hydrochloride and Brimonidinetartrate), etc.), lubricants (including but not limited to saline,polymer solutions, proteoglycans, glycosaminoglycans, carbohydrates,etc., such as found in artificial tears), mydriatic (pupil dilating)agents, iodine derivatives, cholinergic agents (e.g., as described ingreater detail below), including parasymptholytic agents,parasympathomimetic agents and sympathomimetic agents (e.g.,tetrahydrozoline), anti-cholinergic agents, including both long actingand short acting agents (e.g., atropine, tropicamide, etc.), and/orvarious combinations thereof.

In some instances, the ophthalmic agent is a cholinergic agent. The term“cholinergic agent” refers to any active agent that inhibits, enhances,or mimics the action of the acetylcholine, where cholinergic agents mayinclude both nicotinic and muscarinic classes. Cholinergic agentsinclude agents that modulate the parasympathetic nervous system, i.e.,that part of the autonomic nervous system that contracts smooth muscles,dilates blood vessels, increases bodily secretions, and slows the heartrate. In some instances, the cholinergic agent is a miotic agent. Mioticagents are agents that cause contraction of the pupil of the eye. Mioticagents of interest include, but are not limited to, pilocarpine,carbochol, physostigmine, echothiophate, methacholine, moxisylyte andpharmaceutically acceptable salts thereof, and combinations thereof. Insome instances, the cholinergic agent is a muscarinic agonist.Muscarinic agonists are agents that activate the activity of amuscarinic acetylcholine receptor, and in some instances the M₃muscarinic receptor subtype. Muscarinic agonists of interest include,but are not limited to: pilocarpine, carbochol, physostigmine,methacholine, acelidine, arecoline, and cevimeline, and pharmaceuticallyacceptable salts thereof, and combinations thereof. As indicated above,in some instances the cholinergic agent is both a miotic agent and amuscarinic agonist. Where the ophthalmic agent that is delivered to theocular surface is a cholinergic agent, methods and devices as describedherein may be employed to treat any condition for which a cholinergicagent has efficacy.

Additional drugs and agents which may be utilized with the devicesdescribed may include any number of the agents disclosed in furtherdetail in U.S. Pub. 2017/0344714 and U.S. Pat. No. 9,087,145 thedisclosures of which are herein incorporated by reference.

As reviewed above, the liquid formulation includes the ophthalmic agentin a liquid delivery vehicle. The liquid delivery vehicle may be anaqueous delivery vehicle, e.g., a pharmaceutically acceptable aqueousvehicle. In addition to water the aqueous delivery vehicle may include anumber of different components, including but not limited to: salts,buffers, preservatives, solubility enhancers, viscosity modulators,colorants, etc. Suitable aqueous vehicles include sterile distilled orpurified water, isotonic solutions such as isotonic sodium chloride orboric acid solutions, phosphate buffered saline (PBS), propylene glycoland butylene glycol. Other suitable vehicular constituents includephenylmercuric nitrate, sodium sulfate, sodium sulfite, sodium phosphateand monosodium phosphate. Additional examples of other suitable vehicleingredients include alcohols, fats and oils, polymers, surfactants,fatty acids, silicone oils, humectants, moisturizers, viscositymodifiers, emulsifiers and stabilizers. The compositions may alsocontain auxiliary substances, i.e. antimicrobial agents such aschlorobutanol, parabens or organic mercurial compounds; pH adjustingagents such as sodium hydroxide, hydrochloric acid or sulfuric acid; andviscosity increasing agents such as methylcellulose. An exemplary finalcomposition is sterile, essentially free of foreign particles, and has apH that allows for patient comfort and acceptability balanced with a pHthat is desirable for optimum drug stability. An exemplary“pharmaceutically acceptable vehicle” is an “ophthalmically acceptablevehicle” as used herein refers to any substance or combination ofsubstances which are non-reactive with the compounds and suitable foradministration to patient. In an exemplary embodiment, the vehicle is anaqueous vehicle suitable for topical application to the patient's eyes.In various embodiments, the vehicle further includes other ingredientswhich may be desirable to use in the ophthalmic compositions of thepresent invention include antimicrobials, preservatives, co-solvents,surfactants and viscosity building agents. The concentration of thecholinergic agent in a given liquid formulation of a micro-dose mayvary.

In some instances, the liquid formulation is preservative free. By“preservative-free” is meant that the formulations do not include anypreservative agents, such as but not limited to, antimicrobial agentssuch as benzalkonium chloride (BAK), chlorobutanol, sodium perborate,and stabilized oxychloro complex (SOC), parabens and organic mercurialcompounds.

An exemplary final composition is sterile, preservative-free,essentially free of foreign particles, and has a pH that allows forpatient comfort and acceptability balanced with a pH that is desirablefor optimum drug stability. An exemplary “pharmaceutically acceptablevehicle” is an “ophthalmically acceptable vehicle” as used herein refersto any substance or combination of substances which are non-reactivewith the compounds and suitable for administration to patient. In anexemplary embodiment, the vehicle is an aqueous vehicle suitable fortopical application to the patients eyes. In various embodiments, thevehicle further includes other ingredients which may be desirable to usein the ophthalmic compositions of the present invention includeantimicrobials, preservatives, co-solvents, surfactants and viscositybuilding agents.

In some embodiments, the concentration of ophthalmic agent in the liquidformulation of the micro-dose ranges from 50 ng/ml to 100 mg/ml. Forexample, where the cholinergic agent is pilocarpine, the concentrationof pilocarpine in the liquid formulation may range from 5 to 50 mg/ml,such as 10 mg/ml (1%), 20 mg/ml (2%) and 40 mg/ml (4%).

The liquid formulation, e.g., in the form of a micro-dose, may beadministered to the topical ocular location using any convenientprotocol. In some instances, the delivered volume is administered to thetopical ocular location as a stream, where the stream may be acontinuous stream of liquid (i.e., a stream that is not made up ofindividual droplets) or a discontinuous stream of liquid, e.g., acollimated stream of individual droplets, a series of streams, etc. Asthe stream, whether continuous or discontinuous, may be collimated, incertain embodiments the liquid formulation contacts a limited portion ofthe external surface of the eye before spreading across more of the eyesurface, where is some instances the limited contact portion is 50% orless, such as 40% or less, including 30% or less, e.g., 25% or less, 20%or less, 15% or less, including 10% or less, e.g., 5% or less of theexternal surface of the eye. Embodiments of the invention provide foraccurate delivery of the stream to a defined location, such that thestream is precisely administered to a desired location of the ocularsurface. As the stream may be delivered as a collimated stream, in suchinstances substantially all, if not all, of the liquid formulationreleased from the device is delivered to the ocular surface, in contrastto other delivery modalities such as mists and aerosols where not all ofthe fluid emitted from the device reaches the ocular surface, butinstead at least some of which is applied to the surrounding periocularsurfaces. Where the stream is a continuous stream of liquid, the streamdiameter may vary, and in some instances ranges from 0.05 to 0.50 mm,such as 0.070 to 0.130 mm. In some instances, the stream diameter issubstantially constant along its length from its origination point tothe topical ocular location, such that any magnitude of difference indiameter is, in some instances, 1 mm or less, such as 0.5 mm or less,e.g., 0.25 mm or less. In such instances, the stream may be collimated,such that it spreads minimally, if at all, as it propagates from theorifice of the device to the ocular surface. Where the stream is adiscontinuous stream of individual droplets, the volume of theindividual droplets may vary, ranging in some instances from 50 to 1500pl, such as 100 to 1000 pl. Where droplets are administered, thediameter of a given droplet may vary, ranging in some instances from 20to 1000 μm, such as 50 to 750 μm, including 100 to 500 μm. The durationof stream delivery during a given administration event may vary and isselected so as to provide the desired delivered micro-dose, e.g., asdescribed above. In some instances, the duration of stream delivery,i.e., the duration of administration, ranges from 20 to 2000 msec, suchas 50 to 1000 msec, including 75 to 500 msec, such as 50 to 200 msec,including 100 to 150 msec. The volume that is delivered may be varied asa function of pulse duration, where the pulse duration may be fixed orvariable. The velocity of the administered stream may vary and isgenerally above the minimum exit velocity of the fluid from the apertureof the device used to administer the stream, e.g., as described ingreater detail below. The “minimum exit velocity” is as defined inLinblad and Scheider, “Production of uniform-size liquid droplets,” J.Scientific Instruments (1965) 42: 635. (see equation 2 describedtherein). In some instances, the exit velocity is 20% or more above theminimum exit velocity and in some instances is 300% or less above theminimum exit velocity. For example, for an aperture size of 125 micronthe minimum exit velocity is 194 cm/sec but the selected velocity may beat least 30% higher, i.e. at least 252 cm/sec. In some instances, thevelocity ranges from 10 to 500 cm/sec, such as 20 to 250 cm/sec andincluding 50 to 150 cm/sec.

The delivered volume of liquid formulation, e.g., micro-dose, may beadministered to the topical ocular location using any convenientprotocol. In some instances, the delivered volume is administered to thetopical ocular location by an individual other than the subject, e.g.,where the delivered volume is administered by a health careprofessional, such as a physician or nurse or other health careprovider. In other instances, the delivered volume is self-administeredby the subject, e.g., where the subject administers the volume to atopical ocular location of one of the subject's own eyes.

While the nature of the device employed to administer a give volume of aliquid formulation may vary, in some instances the device is a handhelddevice. By handheld device is meant that the device is dimensioned andhas a weight such that it may be comfortably held by an average adulthuman hand. In some instances of handheld devices, the device has alongest dimension ranging from 10 to 500 mm, such as 20 to 250 mm,including 50 to 100 mm, such as 70 to 85 mm, and a weight ranging from10 to 2000 g, including 20 to 1000 g, such as 25 to 500 g, e.g., 40 to100 g.

In some instances the device is one that includes: (1) a containercomprising an amount of the liquid formulation of the cholinergic agentand one or more apertures; and (2) an actuator configured to emit avolume, e.g., micro-dose, of the liquid formulation from the containerthrough the one or more apertures. The container may have any convenientconfiguration, and may be made of any convenient material, e.g., glassor plastic. The container may be configured to hold a single delivereddose or multiple delivered doses, e.g., where the container comprises avolume of the liquid formulation sufficient to provide multipledelivered doses. As such, the volume of liquid formulation that thecontainer is configured to hold may vary, ranging in some instances from100 μl to 10 ml, such as 100 to 2000 μl, including 120 to 800 μl.

The actuator component is a component that imparts energy to the liquidformulation sufficient to produce the desired stream (e.g., as describedabove) by forcing the liquid formulation through the one or moreapertures. In some instances, the actuator is a component that isconfigured to vibration energy to the contents of the container, wherethe oscillation frequency of the vibrational energy may vary. In someinstances, the oscillation frequency is an ultrasonic frequency, rangingin some instances from 20 to 800 KHz, such as 20 to 35 KHz. In someinstances, the frequency is in the audible range, such as from 20 to20000 Hz, e.g., 50 to 10000 Hz, including 500 to 1000 Hz.

While the nature of the actuator component may vary, in some instancesdevices that include an electromagnetic actuator are employed. Inembodiments of such devices, an electromagnetic actuator imparts anoscillation amplitude at low frequency, which in some instances iswithin the audible range (e.g., 20 to 20,000 Hz). In some instances, theelectromagnetic actuator operates in the audio range of frequencies, butproduces low audible tone, generally 30 dB or lower. At the same time,the device emits fluid from a sufficiently large nozzle at sufficientlylow velocity to minimize the discomfort associated with topical deliveryto the eye. Further details regarding such electromagnetic devices areprovided in provisional application Ser. Nos. 62/693,818 filed Jul. 3,2018 and 62/814,773 filed Mar. 6, 2019; the disclosures of which areherein incorporated by reference.

An embodiment of an electromagnetic actuated device is illustrated inFIGS. 100 to 300. Referring to FIG. 100, which illustrates theelectromagnetic dispensing device (100) of the present invention, device(100) includes an ampoule (103) containing a fluid to be dispensed andfurther includes an electromagnetic transducer (113) that is configuredto oscillate the ampoule such that the fluid is dispensed throughaperture (116 at the lower part of the ampoule.

Transducer (113) comprising a base plate (101), electromagnet (115) anda permanent magnet (109). Electromagnet (115) comprising a ferromagneticcore pin (110) and a coil (108) that is wound around the core pin.Permanent magnet (109) is positioned in a close proximity to theelectromagnet core pin (110) and is suspended by a flexible cantileverbeam (106). An alternating magnetic field generated by coil (108)produces magnetic force and mechanical oscillations of permanent magnet(109) and the flexible cantilever beam (106) that supports it.Cantilever beam includes an anchor (107) which support and transmits theoscillation of the cantilever beam to the ampoule. The device furtherincludes a standoff support pin (102) that extends from the base plate(101) and provides a support to the cantilever beam (106).

In the illustrated embodiment, permanent magnet (109) is positioned atthe free end of cantilever beam at a distance of (d2) from thecantilever beam support (102) while the ampoule support anchor (107) isat a distance of (d1) from the beam support (102). In this way amechanical advantage is obtained, and the force applied to the ampule isamplified by the ratio of the distances d2/d1 relative to the forceapplied to the permanent magnet. In the illustrated embodiment theampoule contains 1 mL of aqueous solution and has a mass of approx. 1gm. Accordingly, the force that is required to oscillate the ampoule atan amplitude of approximately 20-60 mm is about 0.2 N to 1 N. In theillustrated embodiment, the distance d2 is 13.5 mm and distance d1 is1.35 mm. The ratio d2/d1 is about 10, and the oscillation amplitude isbetween 20 μm to 60 μm, depending on the input voltage. In theillustrated embodiment, the diameter of the dispensing aperture rangesbetween 200 μm and 350 μm, and such large aperture dispenses only athigh oscillation amplitude.

In the illustrated embodiment the ferromagnetic core (110), base plate(101) and support pin (102) are made of a soft magnetic material, suchas 4750 alloy, or other alloys that have low corrective force andminimal magnetic hysteresis can be used.

Ampoule (103) is oriented such that the dispensing nozzle (116) isaligned with the oscillation amplitude of the cantilever beam (106). Theoscillations generate pressure fluctuation inside the ampoule and fluidis ejected from nozzle (116) as illustrated by the arrow (105)

Permanent magnet (109) may be made of a rare-earth magnetic material,such as Neodymium N35, N38, N42, Samarium Cobalt or the like.Non-rare-earth alloy such as iron, nickel and cobalt may also be used.

Referring now to FIG. 200, this figure shows magnetic transducer (100)and further includes a diagram of the electrical circuit that generatesalternating electrical signal from a DC source, such as a battery cell.

Electromagnetic transducer (100) includes a circuit (100A) whichproduces alternating current which is fed to the coil (108) to generatea magnetic force which oscillates permanent magnet (109). Coil (108)defines two separates magnetic coils, the first is primary coil (108A)and the second is detection coil (108B). Both coils (108A) and (108B)are wound around the iron core (110). When DC voltage is connected tothe primary coil (108A) current flows and the electromagnetic force thatis developed pulls permanent magnet (109) toward core (110). At the sametime the current in the primary coil (108A) produces transient,time-dependent electromagnetic induction, which induces electromotiveforce (EMF) and electrical current in the detection coil (108B), thecurrent is fed to a bipolar transistor (Tr) which switches off thecurrent from the primary coil (108A) by pulling it to the ground (130).As a result, magnetic force returns to zero and magnet (109) return toits normal position. Subsequently, primary coil (108A) turns on againand pulls back the magnet. In this way the alternating magnetic field isgenerated using a DC input voltage from a DC battery. Transistor (Tr) isan NPN general purpose amplifier, such as Fairchild model 2N3904. Thecircuit further includes a Zener diode (D1) that regulates the voltage.Magnetic coil (108A) and (108B) have an inductance that ranges from 1-10mH and are configured to generate a magnetic field to oscillate themagnet (109). Generally, the mass of magnet (109) is small to reduce theinertial load and increase the oscillation amplitude. In one embodiment,the mass of permanent magnet (109) is 0.075 gm. Beam (106) is made ofstainless steel alloy 304 having a thickness of 0.2 mm, a width of 5 mmand a free length of 13.5 mm. In the illustrated embodiment, the beamhas a natural frequency of about 523 Hz while the driving frequency ofmagnetic oscillator is about 1100 Hz.

FIG. 300A illustrates an exploded prospective view of the dispensingdevice (100), showing the ampoule (103) and the electromagnetictransducer (113) separately. It can be seen that ampule (103) includes apin member (301) that is inserted into anchor member (107) in a tightinterference fit. In this way the oscillations that are generated by thetransducer are transmitted to the ampoule.

Where desired, e.g., to provide for a preservative free liquidformulation (such as described above, the device may include a closurefor selectively sealing the aperture when fluid is not being ejectedtherethrough. In such instances, the actuator may be configured tooperate the closure so as to at least reduce, if not prevent, ingress ofoutside materials or contaminants into the reservoir, such that theophthalmic formulation present in the reservoir does not require apreservative (e.g., where a preservative-free ophthalmic formulation ispresent in the reservoir). In some instances, the closure includes asealing structure configured to mate with the aperture in a sealingrelationship, where the sealing structure is movable relative to theaperture between a first position that seals the aperture and a secondposition that does not seal the aperture. The sealing structure may haveany convenient configuration. In some instances, the sealing structurehas a conical structure. In such instances, the conical sealingstructure may have a height ranging from 0.5 to 5.0 mm, such as 0.75 to1.5 mm and a bottom diameter ranging from 0.4 to 4.0 mm, such as 1.5 to2.5 mm. In other embodiments, the sealing structure may be a roundedsealing structure, which in some instances may have a half-sphericalstructure, with a bottom diameter ranging from 0.4 to 4.0 mm, such as1.5 to 2.5 mm. Where desired, the sealing structure, e.g., conicalsealing structure, rounded sealing structure, etc., may be present atthe end of an elongated member, which functions to translate motion fromthe actuator to the sealing structure and thereby provide movement ofthe sealing structure relevant to the aperture. The elongated member mayhave any convenient configuration, and may be configured to interactwith one or more additional components to provide or the desired motiontranslation from the actuator to the sealing structure. In someinstances, the elongated member has a rod configuration. In suchinstances, the rod portion may have any convenient dimensions, rangingin length in some instances from 0.5 to 8.0 mm, including 1.0 to 2.5 mmand ranging in diameter in some instances from 0.5 mm to 5.0 mm,including 0.7 to 2.0 mm. When the closure includes a conical sealingstructure positioned at the end of a rod, the closure may be referred toas a pin. The sealing structure, as well as elongated member whenpresent, may be fabricated from any convenient material, includingmetallic or polymeric materials. As illustrated, the fluid package mayhave an expanded region comprising the reservoir and a neck regioncomprising the aperture. In such instances, the sealing structure ispresent in the neck region. The configuration of the sealing structurein the neck region may vary, e.g., depending on how the actuator isconfigured to move the sealing structure relative to the orifice. Insome instances, the sealing structure is present at the end of anelongated member, e.g., as described above. In such instances, a secondend of the elongate structure may be stably associated with attachmentlocation of an inner surface of the neck region, e.g., where theattachment region is movable relative to the orifice so as to providemovement of the elongated member and sealing structure relative to theaperture. An example of such an attachment location is one that is madeup of a flexible material, such as a membrane or diaphragm. In suchinstances, force can be applied from outside the package to provide forthe desired movement of sealing structure relative to the aperture,e.g., between first and second locations. In other embodiments, theelongated member may be operably associated with a lever that extendsthrough an orifice in the neck region. In such instances, the lever maybe moved, e.g., by the actuator, from a location external to the fluidpackage and thereby move the sealing structure in the neck regionrelative to the aperture, as desired. In these embodiments, thedimensions of the lever orifice may vary as desired to accommodate thedimensions of the lever, ranging in some instances from 0.5 to 2.5 mm,such as 1.0 to 1.5 mm. To prevent fluid from leaking from the fluidpackage, the lever may be sealed in the orifice, e.g., with an O-ring.In such embodiments, the lever may be configured not to move into andout of the orifice, but instead pivot relative to the orifice wall.Where desired, a bias element may be provided which biases the sealingstructure into the aperture when fluid is not be ejected through theaperture, such that the sealing structure seals the aperture. Forexample, a spring may be provided which biases the sealing structureinto the aperture unless the actuator is active, such that sufficientforce is applied against the bias to move the sealing structure out ofthe aperture. Further details regarding embodiment of such sealingstructures and their use with delivery devices of the invention may befound in U.S. Provisional Patent Application Ser. No. 62/814,773 filedMar. 6, 2019; the disclosure of which is herein incorporated byreference.

FIGS. 300B to 300D provide more detailed views of a fluid package andoperation of the closure to seal the orifice when fluid is not beingejected from the orifice. In FIG. 300B fluid package (410) is shownoperably coupled to actuator (450). Fluid package (410) includes anexpanded region (415) that includes the reservoir, which is a standardophthalmic bottle, and neck region (420) press fit onto the opening ofthe ophthalmic bottle. The neck region includes aperture plate (425)that includes a single aperture. Also shown is lever (427) that connectsto a closure in the form of pin present inside the neck region. Actuator(450) includes solenoid housing part (460) and drive coil (470) thatmoves lever (427), where lever movement in turn moves the pin from afirst position that seals the aperture to a second position where theaperture unsealed and fluid can be ejected therethrough.

FIG. 300C provides an exploded view of fluid package (410), whichincludes ophthalmic bottle (415) and neck region (420). Neck regionincludes aperture plate (425) and closure member (430), where theclosure member is in the form of a threaded pin having a conical sealingstructure (435) at one end and threads (440). Also shown is groove (445)that is configured to operably mate with lever (427). Lever (427)extends into neck region (420) via orifice (490) and is sealed by O-ring(495).

FIG. 300D provides a cutaway view of fluid package (410) illustratingthe internal assembly thereof. As shown, neck region (420) is fit intothe opening (413) of ophthalmic bottle (415). Spring (442) urges conicalsealing structure (435) of pin closure member (430) against the apertureof aperture plate (425) to seal the aperture. When fluid is to beejected through the aperture, external end (485) of lever (427) is movedtowards the aperture plate which moves the pin and conical structurethereof away from the aperture plate, thereby unsealing the aperture andallowing for fluid to be ejected therethrough. As described generallyabove, the conical sealing structure and/or aperture may include anantimicrobial material.

In yet other embodiments, devices in which the actuator component is apiezoelectric actuator are employed. Examples of piezoelectric actuatordevices that may be employed in embodiments of the invention are furtherdescribed in: U.S. patent application Ser. No. 14/992,975 filed Jan. 11,2016 and published as U.S. Pat. Pub. 2016/0199225; U.S. patentapplication Ser. No. 15/094,849 filed Apr. 8, 2016 and published as U.S.Pub. 2016/0296367; U.S. patent application Ser. No. 15/874,377 filedJan. 18, 2018 and published as U.S. Pub. 2018/0207030; InternationalApplication Ser. No. PCT/US2018/064529 filed Dec. 7, 2018; U.S. Prov.Pat. App. 62/656,552 filed Apr. 12, 2018; and U.S. Prov. Pat. App.62/693,818 filed Jul. 3, 2018; which applications are incorporatedherein by reference.

FIG. 400A and FIG. 400B illustrate a prospective view and an explodedprospective view of piezoelectric actuator fluid dispensing device.Device (400) comprises a piezoelectric clamping actuator (10) andseparable disposable fluid-filled ampule (20). Ampule (20) comprises athin-walled thermoplastic package which includes a bulb section (21) anda neck section (22). Neck section (22) has a cylindrical shape with acircular cross-sectional shape. Other cross-sectional shapes, such as anoval shape, are also possible. One or more apertures (23) are positionedon the wall of the neck section. Piezoelectric clamping actuator (10) isconfigured to clamp the circumference of the neck section (22) adjacentto the aperture (23) while at the same time apply cycles of oscillationsin the clamping direction against the wall of the ampule as illustratedby the arrows (14A) and (15A). Oscillation of ampoule neck (20)cyclically deforms the circular shape of the neck section intoelliptical shape and produce cycles of acoustic pressure in the fluidwithin the neck (22) and ejection of droplets (24) from an aperture(23). In one embodiment, the neck of the ampule (22) is inserted intothe piezoelectric clamping actuator (10) by light force, such as lessthan 10 newtons. Once inserted, the cylindrical neck (22) engages in aninterference fit with the clamp (10) which facilitates transmission ofthe oscillation amplitude to the ampule neck. In some instances, theoscillation amplitude is less than 2 microns.

The above described electromagnetic and piezoelectric mechanisms may beprovided in any convenient device configuration. In some instances, thedevice configuration, in addition to the components described above,includes an alignment system, e.g., which provides for the stream ofliquid formulation to be accurate delivered to a specific location onthe topical surface. In some instances, the alignment system is animage-based alignment system configured to align fluid ejected throughan aperture of the fluid package with a target location, such as atarget ocular location (e.g., as described in greater detail below). Thealignment systems are systems that allow user, such as the subject towhich the fluid is to be administered, to align the aperture with thetarget location such that the ejected fluid is accurately delivered tothe target location upon actuation of the device. The alignment systemis, in some instances, configured so that a user may self-administer thefluid from the device following alignment by the user of the device. Assummarized above, the alignment systems may be image-based alignmentsystems. By “image-based” alignment system is meant that alignment of adelivery device with a target location includes visualization of animage, e.g., a picture or a reflection, by a user, e.g., the subject towhich fluid is delivered during a self-administration protocol.

In some instances, the image-based alignment system is a reflectivesurface (i.e., mirror) image-based alignment system, where such systemsinclude one or more reflective surfaces or mirrors, and in someinstances include a single reflective surface or mirror. In someinstances, the reflective surface has a curved shape which defines afocal point, i.e. comprising a concave mirror.

Typically, the most visible parts of the eye, when looking in a mirror,are the iris, conjunctiva, sclera (through the conjunctiva), and cornea.Ocular tissue in the focal plane of the concave spherical mirror willappear in focus when the mirror is placed at the focal distance (F) fromthat tissue. The focal point (P) is the intersection of the focal planewith the optical axis of the mirror. One method for delivering fluid toa targeted region may generally comprise positioning a reflectivesurface having a curved shape into proximity with the targeted regionlocated upon a surface of an eye until a reflection of the eye in thereflective surface appears focused to a subject, wherein a focal planedefined by the reflective surface is coincident with the eye when thereflection appears focused. Once positioned, the method may includeactuating a fluid delivery assembly to emit a fluid from one or moreapertures so that fluid is delivered to the target location on the eye.

In some instances, the reflective surface defines one or more openingstherethrough. In such systems, the system may also include a fluiddelivery assembly configured to emit a fluid from one or more apertureswhich are aligned with the one or more openings, wherein the system isconfigured to emit the fluid through the one or more openings andtowards or in proximity to the focal point. In some instances, the fluiddelivery assembly is configured to emit a fluid from one or moreapertures which are aligned with one or more openings defined throughthe reflective surface such that the fluid is directed towards or inproximity to the focal plane and upon the targeted region. In anothervariation, a system for aligning a fluid delivery assembly relative to atargeted region on an eye of a subject may generally comprise a concavemirror having a reflective surface, wherein the mirror defines a focalplane and one or more openings through the mirror for fluid delivery,and a fluid delivery assembly configured to emit a fluid from one ormore apertures which are aligned with the one or more openings such thatthe fluid is ejected through the one or more openings and towards or inproximity to the focal plane.

Instead of a concave mirror, the reflective imaging assembly may includea flat mirror coupled with a suitable lens that provides for alignmentby a user, e.g., as described above and in greater detail below.

Whether the reflective surface is curved or flat, the alignment systemmay be configured such that in self-administration protocols where thetarget location is an ocular surface, the user may focus an image of theeye that includes the target location when aligning the fluid deliverydevice. As such, the same eye that includes the target ocular locationis employed by the user to align the fluid delivery device, e.g., byfocusing and centering the eye in the mirror of the alignment system.

The dimensions of the reflective surface of such image-based alignmentsystems may vary, as desired. In some instances, reflective surface hasa longest dimension, e.g., diameter, that ranges from 10 to 30 mm. Insome instances, the dimensions are such that a subject does not view theentire eye that includes the target ocular location in the mirror. Insuch instances, the longest dimension, e.g., diameter, may range from 10to 15 mm, such as 10 mm, 11 mm, 12 mm, 13 mm, 14 mm or 15 mm.

In some embodiments, the fluid delivery devices include a housing withwhich the various components of the device, e.g., as described above,are associated. The housing may have any convenient configuration, andin some instances has a longest dimension ranging from 50 to 100 mm,such as 70 to 85 mm. The housing may have any convenient shape, whereshapes of interest include those that allow for ready handling and useof the device. In some instances, the housing has an approximatelyrectangular cuboid shape. The housing may be fabricated from anyconvenient material, such as a plastic or metal material.

While the various components of the device may be associated with thehousing component in any convenient manner, in some instances the fluidpackage and actuator components are present inside the housing, andleast a portion of the image-based alignment system is associated with asurface of the housing, e.g., so that the image-based alignment systemmay be viewed by a user during use.

In some instances, the housing includes a movable cover, e.g., whichcovers the apertures and/or alignment system when the device is not inuse. The cover may be configured to move between closed and openpositions, where upon moving the cover from the closed to the openposition, the device is transitioned to a configuration where it may beemployed to deliver fluid. In some instances, movement of the cover fromthe closed to the open position may result in the device transitioningfrom an inactive to active state. For example, movement of the coverfrom the closed to the open position may results in activation of theactuator component.

In some instances, the device includes one or more illumination sources.Any convenient illumination source may be employed, where such sourcesinclude, but are not limited to, light emitting diodes (LEDs), and thelike. When present, the illumination source may take a variety ofdifferent configurations. For example, it may be distinct from any othercomponent of the device, such as the alignment system. Alternatively, itmay be associated with another component of the device. For example, itmay be associated with the alignment system of the device, such as atleast partially bounding, if not completely bounding the alignmentsystem of the device. When present, the illumination source may serve avariety of different functions, such as illuminating the target locationin a reflective surface of the alignment system, indicating that thedevice is aligned with the target location, indicating that the deviceis within a predetermined distance of the target location, indicatedthat the device is ready to deliver fluid, indicating the amount offluid in the fluid package (e.g., full, partially full, empty), and thelike.

In some embodiments, illumination is presented as a circular LED, orsingle or multitude of LED lights in optional pattern (e.g. circularpattern around a circular mirror). The LED light(s) are configured toproduce a light reflection on the corneal surface, and will besuperimposed on the reflection of the patient's eye. The lightreflection, as well as the central aperture element, will appear to beoverlayed over the iris and pupil of the patient's eye. How the patientangles the device relative to their eye and the central aperture elementwill determine where the fluid is administered on the eye surface (e.g.on the central cornea or peripheral cornea, or on the conjunctiva). Assuch, in these embodiments the LED provides for accurate delivery of theliquid formation to a defined location of the ocular surface. Wheredesired, the illumination source, e.g., LED, reflection on the cornealsurface may be employed during administration to accurately deliver thedosage to the ocular surface. In some instances, where the dosage isadministered to the ocular surface by administrator other than thepatient, e.g., a care giver, the administrator may observe theillumination source as an indication of alignment, and administer thedosage when the observed reflection on the corneal surface indicatesalignment. For example, where the illumination source is a provided as acontinuous LED ring, or discontinuous pattern, e.g., circle, of distinctLEDs around a mirror, the administrator may observe the reflection ofthe LED(s) on the corneal surface and determine that the device isaligned with a target ocular location when the pupil is in the center ofthe observed reflected LED(s). In some such instances, the reflectivesurface may not be present, and instead just the illumination source ispresent in the device. Where the dosage is self-administered by thepatient, the patient can also employ the reflected LED(s) on the cornealsurface as observed by the patient in the reflective surface tosimilarly determine alignment, e.g., as described in greater detailbelow.

In some instances, the device includes one or more distance sensors. Adistance sensor is a component configured to determine the distancebetween the device and the target location. Any convenient distancesensor may be present, where such sensors include, but are not limitedto, infra-red (IR) sensors, radar sensors, and the like. In someinstances where the device includes a distance sensor, the device mayfurther be configured to provide a signal, such as an auditory or visualsignal, when the determined distance between the device and the targetlocation is within a predetermined range. For example, the device may beconfigured to activate an illumination source, e.g., as described above,when the device is within a predetermined range of the target locationas determined by the distance sensor. In some instances, the device isconfigured to be activated when the determined distance between thedevice and the target location is within a predetermined range. In theabove embodiments, the predetermined range may vary, and in someinstances is between 1 mm and 250 mm, such as 10 mm to 100 mm.

FIG. 500A and FIG. 500B illustrate a device and method for aligning thedispensing stream to the eye of the user in accordance with anembodiment of the invention. Referring to FIG. 500A and FIG. 500B, itcan be seen that dispensing device (800) includes a concave mirror(805), such as a spherical mirror having a radius of curvature (R),which defines the position of the focal point (P) at a focal distance(F) as F=R/2 from the mirror surface. The focal plane of the mirror isperpendicular to its optical axis and crosses it at the focal point (P).The mirror (805) may be spherical or aspherical in shape and may befabricated using any number of materials and techniques. For instance,the mirror (805) may be manufactured from mirrored glass, reflectivecoatings overlaid upon a substrate, any number of reflective metals,etc. which facilitates removal or cleaning of any ejected fluid whichmay be deposited upon the mirror (805).

Mirror (805) is positioned in close proximity in front of dispensingampule (20). Mirror (805) includes a small opening (806) which may becoaxially oriented relative to the stream (24), in one embodiment, fordelivery fluid to the eye. While a single opening (806) is shown in thisembodiment, multiple openings may be used or defined over the surface ofthe mirror (805) to accommodate one or more apertures for fluid ejectionfrom the transducer assembly.

In use, the device (800) is aligned to the user eye such that thevisible parts of the eye (e.g., cornea, iris, sclera, conjunctiva, etc.)are imaged onto the retina. For the image to be in focus, the mirror(805) should be positioned such that the tissue of interest, e.g.,target ocular location, is in the focal plane (or near the focal plane)of the mirror (805). The eye tissue is clearly visible to the user inthe reflection from the mirror (805) when the eye is located at thefocal plane, e.g., when the distance from the mirror (805) to the tissueof interest, e.g., iris (802), is relatively close to the focal distance(F) of the mirror (805). Such an alignment method helps the user toproperly align the dispensing device both in terms of the angle relativeto the eye, its lateral position and in terms of setting the distancefrom the device to the eye. Both are accomplished when the user sees animage of his or her pupil of the eye that includes the target ocularlocation in the center of the mirror and when such image appears infocus. This alignment mechanism takes advantage of the mirror's naturalfocal distance and further provides for magnification of the reflectedeye so that positioning of the eye relative to the assembly isfacilitated, particularly for users whose eyesight may be degraded.

As the radius of curvature of the mirror becomes smaller, the focalpoint becomes relatively closer to the eye, and the magnification ofthis imaging system becomes relatively higher. For instance, a flatmirror (one having an infinite radius of curvature) can provide an imageonly at the distance where the eye can naturally focus onto, which istypically more than about 30 cm from the eye. Due to the double passingof light from the object to the mirror and back to the eye, the minimaldistance from the flat mirror to the eye will be about 15 cm. Holding adevice so far from the eye will require precise angular alignment toensure the proper targeting, and also requires the emitted fluid topropagate over a large distance without much divergence. Both of theserequirements are hard to meet. Therefore, it is advantageous to use aconcave mirror, which places the focal plane closer to the eye. Theoptimal distance ranges from at a short (first) end defined by theconvenience of holding the device without touching the eye lashes, andat a long (second) end defined by the divergence of the emitted fluid,its deviation from the straight line and by the precision of the angularalignment by the user. The latter may be defined as a ratio of theallowable lateral displacement (misalignment) of the emitted fluiddivided by the distance between the ejector and the targeted tissue. Thecloser the device is to the target tissue, the larger is the allowedangle of misalignment, where the emitted fluid will still hit the targetarea, i.e. the easier it will be for the users to hit the target. In onevariation, the optimal range of the distances between the ejector andthe targeted tissue (e.g., cornea) is in the range of, e.g., 10-100 mm,such as 20-100 mm, and including 30-60 mm.

As illustrated in FIG. 500A, emitting stream (24) may be coaxial andparallel with the principle axis (803) of the mirror (805) and/or withthe central longitudinal axis of the iris (802) or in some offset fromthe central, visual axis of the iris (802) as illustrated in FIG. 500B.In this embodiment, the fluid ejected through the opening (806) may beemitted in a direction which is parallel relative to the principle axisor to the central longitudinal axis of the iris (802) so that theejected fluid contacts the eye at a surface region offset from thecentral axis as well, e.g., cornea, conjunctiva. In yet anotheralternative shown in FIG. 500C, the ejected fluid (24) may be emittedfrom the opening (806) which may be centrally located, but the fluid maybe emitted at an angle (Θ) relative to the principle axis of the eye(802).

In another variation, as shown in FIG. 500B, the aperture and opening(806) defined in the mirror (805) may be offset by a distance (807)relative to the principle axis (803). The opening (806) may beaccordingly offset by the same distance from the axis (803). The ejectedfluid (24) may be emitted towards the targeted region on the eye in atrajectory parallel with the principle axis (803).

In yet another variation, as shown in FIG. 500D, the mirror (805) mayentirely omit the opening (806). The fluid delivery assembly may bepositioned adjacent to the mirror (805) rather than located behind aproximal surface of the mirror (805), e.g., located behind the mirror(805) relative to the position of the eye when in use. Thus, theaperture of the fluid delivery assembly may be positioned, e.g., above,below, side, etc. relative to the mirror (805) so that the fluid may beemitted from the aperture at an angle (α) relative to the principle axis(803) and towards the targeted region on the surface of the eye.

In yet another variation, as shown in FIG. 4E, the alignment system mayinclude a combination of a mirror (811) and a lens (812) as analternative to a concave mirror. The mirror (811) may comprise a varietyof various reflective materials or surfaces, e.g., a metallic layer,having a flat surface on its reflective side (813). The distal surfaceof the lens (812), which may also define a flat surface, may bepositioned directly against the reflective surface (813) of the mirror(811) and both the mirror (811) and lens (812) may each define one ormore openings (806) through which the fluid is delivered. The proximalsurface of the lens may be convex (814), as shown. In other variations,fluid delivery assembly may be positioned relative to the mirror (811)and lens (812) assembly as described in other embodiments herein. Inuse, light may be refracted by the lens (812) and reflected from themirror (811) in such a way that the front of the eye (iris (802) orconjunctiva or cornea) is imaged onto the retina. In this arrangement,light scattered from the eye passes twice through the lens (812) beforeand after reflection in the mirror (811).

Regardless of whether the fluid is ejected along the central axis (asshown in FIG. 500A) or offset or at an angle relative to the centralaxis (as shown in FIG. 500B, FIG. 500C and FIG. 500D), the fluid may beemitted from any number of locations along the mirror (805), adjacent tothe mirror (805), or emitted at any number of angles relative to thelongitudinal axis of the iris (802) so that the fluid may be directed tocontact the surface of the patient's eye at any number of predeterminedlocations. For instance, the fluid may come from multiple locations, orfrom multiple apertures from one or more locations over the same ordifferent areas of the mirror, e.g., nasally and temporally at the sametime. Additionally, multiple streams of fluid may be emittedsimultaneously or serially, or both, if so desired.

In some instances, the optimal focal distance of the mirror (805)ranges, e.g., from 30 mm to 60 mm. Accordingly, in such instances theradius of curvature of the mirror ranges, e.g., from 60 mm to 120 mm,respectively. The diameter of the mirror may be selected such that theimage of the iris is easily identified and the pupil is aligned to thecenter of the mirror. For this purpose, the diameter of the mirror maybe slightly larger than a size of the iris and the size may range, e.g.,from 15 mm to 30 mm. Alternatively, the diameter of the mirror may beselected so as to provide an image of only a portion of the eye, and insuch instances may range from 11 to 15 mm, such as 13 mm.

As illustrated in FIG. 600A, FIG. 600B and FIG. 600C, the mirror (805)may be part of the housing of the device and is made of transparentplastic such as polycarbonate and include a reflective metal layer.

As previously disclosed, the alignment mechanism takes advantage of themirror's natural focal distance and further provides for magnificationof the reflected eye so that positioning of the eye relative to theassembly is facilitated. Size of the image of the eye seen in reflectionin the mirror is dependent on the radius of curvature of the mirror(805). The reflection of the eye appears larger to the user viewing themirror (805) when the radius of curvature of the mirror (805) is smallerand vice versa. An example of this is shown in FIG. 600B and FIG. 600Cwhere the radius of curvature of the mirror (805) in FIG. 600B is, e.g.,60 mm, while the radius of curvature of the mirror in FIG. 600C is,e.g., 30 mm. Consequently, the size of the reflected image appearsrelatively larger in FIG. 600C. Accordingly, not only the size but theradius of curvature of the mirror may be varied depending upon thedesired size of the reflected image.

The mirror (805) may be sized, in one embodiment, to have a circularshape when viewed by the patient so that the reflected image of thepatient's eye or iris becomes framed within the mirror (805), as shownin FIG. 600B and FIG. 600C. In other variations, the mirror may beconfigured to have other shapes when viewed, e.g., elliptical, square,triangular, etc. so long as the eye or iris is visible when properlypositioned relative to the assembly. This may be implemented as anindicator to the user that the eye that includes the target location issuitably positioned relative to the opening (806) so that the ejectedfluid may be suitably administered to the patient's eye. Additionally,the mirror (805) may also optionally include any configuration ofmarkers or gradations (810), as shown in FIG. 600B and 6, such as atarget or reticle to further facilitate positioning of the patient'siris relative to the assembly. Although the markers or gradations (810)may not be visible to the user as the surface of the mirror may be outof focus, they may be optionally included to facilitate initialpositioning relative to the user's eye.

In yet another embodiment, an example of a housing assembly (900) isshown in front and side views of FIG. 700A and FIG. 700B, where a bodyof the housing (902) may incorporate one or more gripping surfaces (904)upon or around the housing (902). The assembly (900) has a form factorwhich facilitates the user holding and/or positioning the devicerelative to the tissue target of interest, such as one or both eyes, byenabling the user to comfortably hold and manipulate the device with asingle hand. The housing assembly (900) may accordingly contain and/orenclose the various components of the actuator assembly (906) such asthe piezoelectric actuator and actuator controller as well as theampule, alignment assembly, etc.

With the gripping surfaces (904) thus defined, the one or more aperturesthrough which the fluid is ejected may be positioned in alignment withan opening, slot, or slit (908) defined along the device through whichthe fluid may pass. Additionally, the assembly may incorporate any ofthe alignment mechanisms described. In this variation, the alignmentmirror (910) is shown to illustrate how such a mechanism may beincorporated into the assembly where the mirror (910) defines theopening, slot, or slit (908) which is in proximity to the one or moreapertures. The alignment mirror (910), or any of the other alignmentmechanisms, may be incorporated into the assembly (900) and used toenable the user to self-align the one or more apertures to the targetedtissue region and administer fluid delivery for treatment.

As previously described, the size, orientation, and/or location of theone or more apertures may vary. Furthermore, multiple apertures and/oraperture geometries (such as a slit to create a “plane” of fluid) may beoptionally incorporated.

The housing (902) may also incorporate an actuator (912), such as abutton, switch, or other actuation mechanism to begin the dispensing ofthe fluid. The actuator (912) is illustrated in this embodiment as abutton-type located atop the housing (902) so that the user may depressthe actuator (912) during use; however, the actuator (912) may bepositioned elsewhere along the housing (902). Additionally, and/oroptionally, the aperture (908) may incorporate a shutter or othercovering which may open or close when actuated such as by activating theactuator (912).

Another component of the housing assembly (900) may include a coverelement (914) which may be moved between a closed and opened position,as indicated by the direction of movement (918). In its closed position,the cover (914) may partially or completely cover or obstruct thealignment mechanism and aperture as well as optionally deactivate theassembly so that fluid is prevented from being dispensed. In its openposition, the alignment mechanism and aperture may be unobstructed foruse and the assembly may be activated or powered on for dispensing thefluid.

In this variation, the cover element (914) is configured as a slidingcover which may be translated within a channel or groove (916). Slidingthe cover into its open position, as shown, exposes the mirror (910),the opening (908) and one or more apertures, and may also power thedevice on. Sliding the cover into its closed position may slide thecover over the mirror (910), opening (908), and may further deactivatethe assembly. While the cover is shown as a sliding mechanism, othervariations may incorporate a rotating cover or a cover which may beremoved entirely as a separate or coupled structure. Additionally,during use, the cover element (914) may also serve as a thumb-rest, suchthat the patient uses his/her own thumb as a brace against his/her cheekto stabilize and align the device during use.

FIG. 800 provides a view of another embodiment of a fluid deliverydevice in accordance with the invention. As shown in FIG. 800, device(1000) includes a housing (1010) having a sliding cover (1020). Presentin the housing is a fluid delivery package and actuator, e.g., asdescribed above. As shown, the device (1000) includes an actuator button(1030) on the top of the housing. The device also includes aconcave-mirror image-based alignment system (1040) as described above,where the concave mirror (1050) includes an opening (1060) through whichfluid ejected from the aperture may flow during fluid delivery.Surrounding or bounding the concave mirror (1050) is circular LED(1070), e.g., as described above. Also shown is IR sensor (1080).Further details regarding the handheld device depicted in FIG. 800 areprovided in International Application Ser. No. PCT/US2018/064529 filedDec. 7, 2018; the disclosure of which is herein incorporated byreference.

Aspects of the invention further include systems that include a deviceof the invention, e.g., as described above, or components thereof, incommunication with one or more networked devices. As such, systems ofthe invention may include a delivery device such as described above incommunication with a networked device, where the delivery deviceincludes a transmitter, e.g., for communicating with a networked device.A networked device is any device that communicates with at least oneother device over a communication link, and in the present invention isa device that includes a communications module that is configured tocommunicate with the communications module of the delivery device,either directly or via one or more intermediate devices. Networkeddevices that may be part of a system of the invention may vary, wheresuch devices include, but are not limited to: desktop computing devices,intermediate computing devices, mobile devices (e.g., laptop, cell phoneor other mobile computing devices), servers (which may be local orremote), etc. The communication link may vary, where the communicationlink may be a wired or wireless communication link. Wired communicationlinks may include USB, FireWire, HDMI, Ethernet, LAN, and the like.Wireless communication links that may be employed include, but are notlimited to, those employed in any suitable communications network, suchas but not limited to wireless personal area networks (WPANs) (e.g.,Bluetoooth, ZigBee), wireless local area networks (WLANs) (WiFi),wireless ad hoc networks, wireless metropolitan area networks, wirelesswide area networks, cellular networks, global area networks, etc. Insuch instances, a variety of different types data may be transmittedbetween the delivery device and the one or more networked devices.Examples of types of data that may be transmitted include, but are notlimited to: usage information, such as confirmation that a dose has beendelivered, including temporal information, e.g., date and/or time, ofdose delivery; information about the status of the device, e.g., numberof doses that have been administered, number of doses remaining,operational information about the device (e.g., battery life,functionality, etc.); and the like.

In some aspects, in addition to administration of one or more doses,e.g., micro-doses, the method further comprises the step of measuringefficacy of a given therapy for a condition, e.g., of a diseasecondition in the subject. In some such instances, the determination ismade by comparing the results to the results performed on the sameindividual at an earlier time, e.g., 2 weeks earlier, 1 month earlier, 2months earlier, 3 months earlier, 6 months earlier, 1 year earlier, 2years earlier, 5 years earlier, or 10 years earlier, or more. Theevaluation may vary depending on the nature of the condition beingtreated. In some embodiments, the subject methods further includediagnosing an individual as having a given condition. Conditions ofinterest include those further described below.

As used herein, the terms “host”, “subject”, “individual” and “patient”are used interchangeably and refer to any mammal in need of suchtreatment according to the disclosed methods. Such mammals include,e.g., humans, ovines, bovines, equines, porcines, canines, felines,non-human primate, mice, and rats. In certain embodiments, the subjectis a non-human mammal. In some embodiments, the subject is a farmanimal. In other embodiments, the subject is a pet. In some embodiments,the subject is mammalian. In certain instances, the subject is human.Other subjects can include domestic pets (e.g., dogs and cats),livestock (e.g., cows, pigs, goats, horses, and the like), rodents(e.g., mice, guinea pigs, and rats, e.g., as in animal models ofdisease), as well as non-human primates (e.g., chimpanzees, andmonkeys).

The above methods find use in a variety of different applications.Certain applications are reviewed in greater detail in the Utilitysection, below.

Utility

The subject methods and devices find use in a variety of differentapplications, including treatment applications. The term “treating” or“treatment” as used herein means the treating or treatment of a diseaseor medical condition in a subject or patient, such as a mammal (such asa human), where the term includes: (a) preventing the disease or medicalcondition from occurring, such as, prophylactic treatment of a subject;(b) ameliorating the disease or medical condition, such as, eliminatingor causing regression of the disease or medical condition in a patient;(c) suppressing the disease or medical condition, for example by,slowing or arresting the development of the disease or medical conditionin a patient; or (d) alleviating a symptom of the disease or medicalcondition in a patient.

Presbyopia

An example of a condition that may be treated using methods/devices ofthe invention is presbyopia. Presbyopia is the impairment of vision dueto advancing years or old age and may be characterized by the gradualloss of the ability to focus on nearby objects. Presbyopia may bediagnosed using one or more types of ocular examination procedures,where such examinations may include testing of one or more of visualacuity, e.g., by use of a Snellen chart, Jaeger chart, Rosenbaum chartor ETDRS Near Chart, refraction, binocular vision and accommodation,plus lens to clear near vision, balanced range of accommodation,amplitude of accommodation, crossed cylinder test, accommodativeconvergence/accommodation, heterophoria and vergence, and verticalimbalance.

In the treatment of presbyopia, the devices and methods may be used todeliver a cholinergic agent, e.g., as described above, to a topicalocular location. As reviewed above, the term “cholinergic agent” refersto any active agent that inhibits, enhances, or mimics the action of theacetylcholine, where cholinergic agents may include both nicotinic andmuscarinic classes. Cholinergic agents include agents that modulate theparasympathetic nervous system, i.e., that part of the autonomic nervoussystem that contracts smooth muscles, dilates blood vessels, increasesbodily secretions, and slows the heart rate. In some instances, thecholinergic agent is a miotic agent. Miotic agents are agents that causecontraction of the pupil of the eye. Miotic agents of interest include,but are not limited to, pilocarpine, carbochol, physostigmine,echothiophate, methacholine, moxisylyte and pharmaceutically acceptablesalts thereof, and combinations thereof. In some instances, thecholinergic agent is a muscarinic agonist. Muscarinic agonists areagents that activate the activity of a muscarinic acetylcholinereceptor, and in some instances the M₃ muscarinic receptor subtype.Muscarinic agonists of interest include, but are not limited to:pilocarpine, carbochol, physostigmine, methacholine, acelidine,arecoline, and cevimeline, and pharmaceutically acceptable saltsthereof, and combinations thereof. As indicated above, in some instancesthe cholinergic agent is both a miotic agent and a muscarinic agonist.

When used in the treatment of presbyopia, the methods may result in theimprovement of one or more characteristics of presbyopia. For example,methods of the invention may result in a reduction in pupil diameter ascompared with reduction in pupil diameter observed prior to cholinergicagent administration. The magnitude of the reduction may vary, and insome instances may range from 0.25 to 10 mm, such as 1 to 9 mm,including 2 to 8 mm, where in some instances the reduction ranges from0.25 to 3.0 mm, such as 0.5 to 1.5 mm, including 0.5 to 1.0 mm. In someinstances, the methods may result in an improvement in uncorrected nearvisual acuity or other measures of visual function including uncorrectedintermediate or distance vision, contrast sensitivity or depth of focus,amongst other measures. Where visual acuity is measured using a chart,such as a Jaeger or Rosenbaum near card, Snellen card or ETDRS NearChart, the methods may result in an improvement of one or more lines onthe chart, such as 1 to 8 lines, including 2 to 6 lines. In someinstances, magnitude of improvement with respect to a letter than can beread at 20 feet is 5 feet or more, such as 10 feet or more, including 15fee or more, where the magnitude ranges in some instances from 5 to 60feet, such as 5 to 30 feet, e.g., 10 to 25 feet, including 15 feet,e.g., where visual acuity improves from 20/40 to 20/25 or 20/20.

When used in the treatment of presbyopia, the methods of the inventionin which a micro-dose is delivered to a topical ocular location mayresult in at least a reduction, if not substantial or completeelimination, of one or more adverse effects of the administered activeagent, such as but not limited to: temporary irritation/burning/stingingof the eye, ocular inflammation, ciliary spasm, temporary blurredvision, poor vision in dim light, headache, brow ache, etc.

Dry Eye Disease An example of another condition that may be treatedusing methods/devices of the invention to deliver a cholinergic agent isdry eye disease. Keratoconjunctivitis sicca (KCS), also called keratitissicca, sicca syndrome, xerophthalmia, dry eye syndrome (DES),or simplydry eyes, is an eye disease caused by decreased tear production,increased tear film evaporation, or Meibomian gland dysfunction,commonly found in humans, most often post-menopausal females, and someanimals. Typical symptoms of keratoconjunctivitis are dryness, burningand a sandy, gritty eye irritation that gets worse as the day goes on.Keratoconjunctivitis sicca is characterized by inadequate tear filmprotection of the cornea because of either inadequate tear production orabnormal tear film constitution, which results in excessively fastevaporation or premature destruction of the tear film. The tear film isconstituted by 3 layers: (1) a lipid layer, produced by the Meibomianglands; (2) an aqueous layer, produced by the main and accessorylacrimal glands; and (3) a hydrophilic mucin layer, produced by theconjunctival goblet cells. Any abnormality of 1 of the 3 layers producesan unstable tear film and symptoms of keratitis sicca.Keratoconjunctivitis sicca can also be caused by abnormal tearcomposition resulting in rapid evaporation or premature destruction ofthe tears. When caused by rapid evaporation, it is termed evaporativedry eyes. In this, although the tear gland produces a sufficient amountof tears, the rate of evaporation of the tears is too rapid. There is aloss of water from the tears that results in tears that are too “salty”or hypertonic. As a result, the entire conjunctiva and cornea cannot bekept covered with a complete layer of tears during certain activities orin certain environments.

In embodiments where the methods and devices are used in treating dryeye disease, the delivered micro-dose may include a cholinergic agent,e.g., as described above, effective to reduce the intraocular pressureso as to treat the subject for the dry eye disease. In addition oralternatively, in treating dry eye the delivered micro-dose may includean anti-inflammatory/immunomodulatory/immunosuppressive agent, e.g. aCyclosporine, such as Cyclosporine A and derivatives thereof; FK-506,Rapamycin, Buspirone, Spiperone, and/or their derivatives, etc. In onesuch embodiment, the administered micro-dose is an emulsion includingwater, a hydrophobic component and a cyclosporin component, e.g., suchas described in U.S. Pat. Nos. 8,629,111; 8,633,162; 8,642,556;8,648,048; 8,685,930; and 9,248,191; the disclosures of which are hereinincorporated by reference, e.g., Restasis® Cyclosporine ophthalmicemulsion. In some embodiments, the active agent administered bymicro-dose is an anti-inflammatory agent, such as lifitegrast, e.g., asdescribed in U.S. Pat. Nos. 7,314,938; 7,745,460; 7,790,743; 7,928,122;8,048,047; 8,168,655; 8,367,701; 8,592,450; 8,927,574; 9,085,553;9,216,174; 9,353,088; 9,447,077; 9,890,141 and 10,124,000; thedisclosures of which are herein incorporated by reference, e.g., Xiidralifitegrast ophthalmic solution. In some instances, the micro-doseincludes a steroid active agent. such as Corticosteroids, such asPrednisolone, Prednisolon, Dexamethasone, Loteprednol, Difluprednate,Fluorometholone, Rimexolone and Medrysone, etc. In some instances, themicro-dose is a micro-dose of an artificial tears, including low andhigh viscosity artificial tears, where artificial tears includeophthalmic formulations containing carboxymethyl cellulose, polyvinylalcohol, hydroxypropyl methylcellulose (a.k.a. HPMC or hypromellose),hydroxypropyl cellulose and hyaluronic acid (a.k.a. hyaluronan, HA),etc., where compositions may further contain water, salts and polymersbut lack the proteins found in natural tears. Where the deliveryformulation is highly viscous, devices as describe herein may beparticularly suited for delivery of such formulations, as the orifice ofthe device may be sized to avoid clogging of the orifice by the highlyviscous formulation.

The methods may result in improvement of one or more symptoms of the dryeye disease, which symptoms may include, but are not limited to: foreignbody sensation or irritation, staining of the ocular surface/epitheliumwith sodium fluorescein or rose bengal, deficiency of tears (aqueousdeficiency) (as measured by Schirmer's testing), reduced vision, reducedtear break up time, reflex tearing, increased osmolarity of the tearfilm, meibomian gland dysfunction, conjunctival redness/injectionstaining of the ocular surface with lisamine green, etc.

When used in the treatment of dry eye, the methods of the invention inwhich a micro-dose is delivered to a topical ocular location may resultin at least a reduction, if not substantial or complete elimination, ofone or more adverse effects of the administered active agent, such asbut not limited to: eye burning, redness, tearing, discharge, pain,itching, stinging, visual blurring, feeling as if something is in theeye, conjunctival hyperemia, headache, increased lacrimation, eyepruritus and sinusitis, etc.

Sjogren's Syndrome

An example of another condition that may be treated usingmethods/devices of the invention to deliver a cholinergic agent isSjogren's syndrome. Sjogren's syndrome and autoimmune diseasesassociated with Sjogren's syndrome are also conditions associated withaqueous tear deficiency. Drugs such as isotretinoin, sedatives,diuretics, tricyclic antidepressants, antihypertensives, oralcontraceptives, antihistamines, nasal decongestants, beta-blockers,phenothiazines, atropine, and pain-relieving opiates such as morphinecan cause or worsen this condition. Infiltration of the lacrimal glandsby sarcoidosis or tumors, or post-radiation fibrosis of the lacrimalglands can also cause this condition. In embodiments where the methodsand devices are used in treating Sjogren's syndrome, the deliveredmicro-dose may include a cholinergic agent, e.g., as described above,effective to reduce the intraocular pressure so as to treat the subjectfor Sjogren's syndrome.

Other conditions include, but are not limited to, those characterized bymiscellaneous refractive errors, including hyperopia, astigmatism,post-surgical optical aberrations, e.g., following cataract surgery,LASIK, PRK, corneal transplantation etc., as well as other conditionswhere a pinhole effect may be beneficial with respect to the condition.

Glaucoma

An example of another condition that may be treated usingmethods/devices of the invention is glaucoma. Glaucoma is a collectionof disorders characterized by progressive visual field loss due to opticnerve damage. It is the leading cause of blindness in the United States,affecting 1-2% of individuals aged 60 and over. Although there are manyrisk factors associated with the development of glaucoma (age, race,myopia, family history, and injury), elevated intraocular pressure, alsoknown as ocular hypertension, is the only risk factor successfullymanipulated and correlated with the reduction of glaucomatous opticneuropathy. In glaucoma associated with an elevation in eye pressure thesource of resistance to outflow is in the trabecular meshwork. Thetissue of the trabecular meshwork allows the “aqueous” to enterSchlemm's canal, which then empties into aqueous collector channels inthe posterior wall of Schlemm's canal and then into aqueous veins. Theaqueous or aqueous humor is a transparent liquid that fills the regionbetween the cornea at the front of the eye and the lens. The aqueoushumor is constantly secreted by the ciliary body around the lens, sothere is a continuous flow of the aqueous humor from the ciliary body tothe eye's front chamber. The eye's pressure is determined by a balancebetween the production of aqueous and its exit through the trabecularmeshwork (major route) or via uveal scleral outflow (minor route). Thetrabecular meshwork is located between the outer rim of the iris and theinternal periphery of the cornea. The portion of the trabecular meshworkadjacent to Schlemm's canal causes most of the resistance to aqueousoutflow (juxtacanalicular meshwork). In embodiments where the methodsand devices are used in treating glaucoma, the delivered micro-dose mayinclude a cholinergic agent, e.g., as described above, effective toreduce the intraocular pressure so as to treat the subject for theglaucoma. In some instances, the glaucoma is angle-closure glaucoma. Insome instances, the condition is acute angle-closure glaucoma and inother instances, the condition is chronic angle-closure glaucoma”.

In treating glaucoma, in some instances the ophthalmic agent is acholinergic agent, e.g., as described above. Also of interest intreating glaucoma is the use of intraocular pressure modulatory agents,such that in some instances the methods/devices of the invention deliveran intraocular pressure modulatory agent to treat glaucoma. An“intraocular pressure modulatory agent” can comprise a drug and may beany of the following or their equivalents, derivatives or analogs:agents that work to increase the outflow of fluid (aqueous humor) fromthe eye, e.g., prostaglandin active agent, such as prostaglandinanalogues, such as bimatoprost, travoprost, tafluprost, latanoprost,etc., including Xalatan® (latanoprost), Lumigan® (bimatoprost), TravatanZ® (Travoprost), and Zioptan™ (tafluprost), and Vyzulta™ (latanoprostenebunod); agents that work to decrease fluid (aqueous humore) production,e.g., beta blockers, such as timolol, betaxolol, levobunolol, atenolol(e.g., as described in U.S. Pat. No. 4,952,581); agents that work toboth decrease fluid production and increase drainage, e.g., alphaagonists, such as apraclonidine or brimonidine (e.g., as described inU.S. Pat. No. 5,811,443) e.g., Alphagan®P (brimonidine), Iopidine®;agents that decrease production of intraocular fluid, e.g., carbonicanhydrase inhibitors (CAIs), e.g., acetazolamide, dorzolamide,brinzolamide, methazolamide, dichlorphenamide, diamox, and the like,such as Trusopt® (dorzolamide), Azopt® (brinzolamide), etc.; agents thatincrease the drainage of fluid, such as Rho kinase inhibitors, e.g.,Rhopressa® (netarsudil); and combination therapies, e.g., Cosopt® (acombination of a beta blocker (timolol) and a carbonic anhydraseinhibitor (dorzolamide)) and a preservative-free formulation thereof(Cosopt® PF); Combigan® (a combination of an alpha agonist (brimonidine)with a beta blocker (timolol); and Simbrinza® (a beta blocker-freecombination medication consisting of brinzolamide and brimonidine); etc.In some instances, the therapeutic agent is already marketed forglaucoma, and commercially available preparations thereof can be used.

When used in the treatment of glaucoma, the methods of the invention inwhich a micro-dose is delivered to a topical ocular location may resultin at least a reduction, if not substantial or complete elimination, ofone or more adverse effects of the administered active agent, such asbut not limited to: change in iris color and growth of eyelashes,blurred vision, double vision, drooping eyelid, burning or stinging inyour eye, eye itching or redness, watery eyes, feeling as if somethingis in the eye, headache, weakness, drowsiness, numbness, tingling, coldfeeling in your hands or feet, ringing in ears, dry mouth, nausea,diarrhea, loss of appetite, upset stomach, skin rash or worseningpsoriasis, sleep problems (insomnia), cough, stuffy nose, bradycardia,exacerbation of asthma, eye redness, corneal abnormalities, instillationsite pain, burst blood vessels in the eye, eyelid skin darkening,browning of the iris, increased sensitivity to light, oozing or eyedischarge, fat atrophy, etc.

Myopia

Aspects of the invention also include treatment and/or prevention ofmyopia. Myopia is the condition known as “near-sightedness”, where theimage in front of the eye is focused in front of the retina rather thanexactly on the retina. This focus of the image on the retina is alsoreferred to as “emmetropia”. The image in myopia may be focused in frontof the retina for one or both of the following reasons: either therefractive strength of the front of the eye at the cornea and lens isexcessive; and/or the axial length of the eye is too long, such that theretina is posterior to the image focal point, causing blurred vision. Tocounteract this visual blurring, those affected move closer to theobject to be viewed. This moves the focal point of the image back andcloser to the retina, causing the vision to become more clear. Methodsof the invention may be employed prevent the occurrence of myopia, ormodulate, such as inhibit or slow down, the progression of myopia.

In such instances, anti-cholinergic agents, including both long actingand short acting agents (e.g., atropine, tropicamide, etc.), such asdescribed above, may be administered to the subject.

When used in the treatment of myopia, the methods of the invention inwhich a micro-dose is delivered to a topical ocular location may resultin at least a reduction, if not substantial or complete elimination, ofone or more adverse effects of the administered active agent, such asbut not limited to: eye pain and stinging, blurred vision, photophobia,superficial keratitis, decreased lacrimation, etc.

Other Disease Conditions

Other disease conditions that may be treated by methods and devices ofthe invention include, but are not limited to, those described in U.S.Pub. 2017/0344714 and U.S. Pat. No. 9,087,145 the disclosures of whichare herein incorporated by reference.

Diagnostic/Examination Applications

Diagnostic/examination applications include, but are not limited to,mydriasis applications where the pupil is dilated, e.g., to permitexamination of the retina and other deep structures of the eye.Mydriatic agents that may be employed in such applications include, butare not limited to: atropine, atropine sulfate, atropine hydrochloride,atropine methylbromide, atropine methylnitrate, atropine hyperduric,atropine N-oxide, phenylephrine, phenylephrine hydrochloride,hydroxyamphetamine, hydroxyamphetamine hydrobromide, hydroxyamphetaminehydrochloride, hydroxyamphetamine iodide, cyclopentolate, cyclopentolatehydrochloride, homatropine, homatropine hydrobromide, homatropinehydrochloride, homatropine methylbromide, scopolamine, scopolaminehydrobromide, scopolamine hydrochloride, scopolamine methylbromide,scopolamine methylnitrate, scopolamine N-oxide, tropicamide, tropicamidehydrobromide, and tropicamide hydrochloride.

Kits

Also provided are kits that find use in practicing embodiments of themethods, such as those described as described above. The term “kit”refers to a packaged delivery device or component thereof, e.g., ampule,such as described above. In addition to the above-mentioned components,kits may further include instructions for using the components of thekit, e.g., to practice the subject method. The instructions aregenerally recorded on a suitable recording medium. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or sub-packaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, Hard Disk Drive (HDD), portable flash drive, etc. Inyet other embodiments, the actual instructions are not present in thekit, but means for obtaining the instructions from a remote source, e.g.via the internet, are provided. An example of this embodiment is a kitthat includes a web address where the instructions can be viewed and/orfrom which the instructions can be downloaded. As with the instructions,this means for obtaining the instructions is recorded on a suitablesubstrate.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES I. Treatment of Presbyopia

A 10 μl micro-dose of a 1% pilocarpine solution was self-administeredusing an electromagnetic actuated fluid delivery device, e.g., asdescribed above, by three subjects to their own eye. The age range ofthe subjects was 52 years to 68 years, and all subjects were male. Thepilocarpine micro-dose was self-administered by the subjects.

Baseline, pre-dose values of pupil diameter and near visual acuity inboth eyes prior to dosing was measured for all subjects, and thenfollowing the baseline measurements, the subjects were dosed in only oneeye (the eye with the poorer visual acuity) with the micro-dosepilocarpine solution. Approximately 45 to 60 minutes after dosing, pupildiameter and near visual acuity were again tested. Near visual acuitywas measured using a Snellen card at a distance of 40 cm. A tabulationof results is given below in Table A.

TABLE A Subject 1-3 mean SD Mean Age (yrs) 58.3 8.5 Mean baseline pupildia dosed eye (mm) 2.9 0.62 Mean baseline pupil dia non-dosed eye (mm)2.8 0.9 Median baseline near visual acuity 20/30 n/a Mean post-dosepupil dia (mm) 2.2 0.81 Mean change in dosed pupil dia (mm) −0.7 0.2Mean non-dose pupil dia (mm) 3.0 0.6 Mean change in non-dosed pupil dia(mm) 0.2 0.5 Median dosed eye near visual acuity 20/20 n/a # of lineschange in visual acuity 2 1

As can be seen in the data summary, the non-dosed eye experienced nomiotic effect, there was no reduction in pupil diameter. The dosed eyeexperienced a substantial miotic effect in all subjects with a meanreduction in pupil diameter of 0.70 mm (range 0.43 to 0.80 mm).Additionally, the dosed eye experienced a substantial improvement innear visual acuity in all subjects with a mean improvement of 2 lines(range 1 to 3 lines).

II. Treatment of Glaucoma A. Introduction

Glaucoma affects over 60 million people globally and is the secondleading cause of blindness. It has been estimated that nearly 3 millionpeople have glaucoma in the United States alone. Topical ocular medicaltherapy has been and continues to be essential for the control ofintraocular pressure (IOP), a major risk factor for the development ofoptic neuropathy. Over the past three decades, difficulty withself-administration of eye drops has been well documented in theclinical literature, many of whom are patients with glaucoma or ocularhypertension (OHT). Problems that are reported with high prevalence forself-administration include missing the eye due to poor technique, andcontamination resulting from touching the bottle tip to the eye. Inaddition, several of the studies report a mismatch between patientself-perceptions of eye drop technique and actual, objective measures ofproper administration. This is particularly problematic for patientswith glaucoma or ocular hypertension who must use eye drops successfullyevery day to comply with their prescribed therapy.

For practical reasons, eye drop bottles are designed to allow patientsto self-administer with relatively minimal force. In order to achievethis, the orifice diameter is fairly large. However, this leads toincreased drop volumes, which is currently estimated to be approximately30-50 μl per drop from existing topical delivery bottles. Not only isthis more than the required therapeutic dose, it also is more than canbe held physically in the ocular cul de sac. In addition, the excessvolume may drain into the nasolacrimal system, flood the lower eyelidmargin or elicit a strong eye blink reaction which can force fluid fromthe eye surface and may contribute to more side effects.

B. AcuStream™ Device

The AcuStream™ topical ocular drug delivery device prototype employed inthis study was developed by Kedalion Therapeutics (Menlo Park, Calif.)to overcome compliance and dosing adherence obstacles related toself-administration with standard eye drop delivery. Standard dropvolume doses can vary from 30-50 ∥l while the AcuStream™ device deliversa dose volume of approximately 10 μl, corresponding to the fluid volumecapacity of the eye surface. The AcuStream™ device consists of adisposable and sterile drug-filled ampule, a piezoelectric actuator, anda handheld apparatus which houses a battery-powered printed circuitboard, e.g., as further described above. When actuated, the device emitsa low impact, collimated liquid dose to the surface of the eye. Thedevice is designed to overcome the obstacles presented by patientself-administered drug therapy using standard eye dropper bottles. Asmentioned above, the AcuStream™ device is designed to deliver a dose ofapproximately 10 μl which is believed to be sufficient to achieve anequivalent therapeutic effect when compared with standard eye dropinstillation. The low impact drug stream is collimated and intended todeposit the dose to the area between the upper and lower eyelids at animpact velocity believed to be lower than the threshold to initiate ablink reaction. The patient's head is comfortably positioned with theeyes facing straight ahead instead of with the head extended backward aswith eye drops. The AcuStream™ device's piezoelectric actuator isintended to replace the variable squeeze force required for standard eyedrop administration.

C. Pupil Dilation Using Tropicamide & Phenylephrine 1. Objective:

Trial 1 compared the safety, efficacy (dose volume equivalence), andcomfort associated with AcuStream (pre-trial calibration volume=9.2 μl)versus the standard eye dropper (approximate dose volume=30 μl) onpatient volunteers requiring pupil dilation for subsequent retinalexamination using a combination formulation of 1% w/v tropicamide and2.5% w/v phenylephrine to induce mydriasis.

2. Method:

a. Study Population: The study population consisted of 20 male andfemale patients, age 21 years or greater (Table 1), selected from thoseattending the daily retina clinic and all requiring bilateral pupildilation fundus for later fundus examination by means of indirectophthalmoscopy.

TABLE 1 Trial 1 Population Demographics for Post-InstillationMeasurement VALUE Total # of Patients 20* Female 12 (60%) Male  7 (35%)Age (Mean) 57.5 Std Dev 19.37 Std Error  4.44 Median 65.0 Q1, Q3 40.0,72.0 Min, Max   21, 86 *Age and gender were not recorded for one patient

All patients were advised of the study details and signed informedconsent documents in accordance with the Declaration of Helsinki toconfirm agreement to participate. Patients who showed evidence ofcorneal opacities that could interfere with accurate pupil measurements,pupillary defects, anterior chamber synechiae, or who experienced recenttrauma or were diagnosed with diabetic retinopathy were excluded.Patients were also excluded if their baseline pupil diameter exceeded4.0 mm or had a history of open or closed angle glaucoma. Afterscreening, patients were instructed to remain in the clinic area for aperiod of 3 hours for pupil dilation measurements taken at 30-minuteintervals.

b. Study Design:

An acute prospective, randomized, actively controlled and maskedexaminer design comparison of AcuStream™ device delivery of acombination formulation of 2.5% w/v phenylephrine and 1.0% w/vtropicamide with a single drop (via standard dropper) consisting of thesame formulation for pupil dilation was employed for this study. Eachpatient's eyes were randomized by means of a random numbers table; anodd number dictated that the patient's right eye (OD) was assigned the“test” (AcuStream™) eye, while an even number meant that the patient'sleft eye (OS) was the test eye. The contralateral eye served as thecontrol eye (standard eye dropper administration).

c. Procedure:

All patients were seated comfortably while undergoing slit lampexamination of the anterior chamber and fluorescein staining under bluelight illumination. Magnified digital images from a slit lamp mountedcamera were obtained for both eyes as a baseline indicator of cornealepithelial integrity and used for subsequent post treatment comparison.The baseline pupil diameters for each eye were measured by a sole maskedexaminer utilizing the automated Neurotech 3000 Pupillometer (Neurotech,Inc.) with an empirically determined accuracy of ±0.3 mm. The ambientlighting level was set at 50 mW/cm² and stray light was minimizedthrough the use of device mounted eyecup resting firmly, butcomfortably, at the eye orbit margins. The eyecup stabilized the deviceposition and maintained a constant vertex distance. The pupil diameterwas measured continuously for 5 sec with the result averaged over thattime interval and immediately recorded.

The mydriatic formulation was administered by a sole ophthalmologist toeach eye and digitally recorded via GoPro 5 for later comparisonanalysis. Patients were requested to look up slightly because theophthalmologist was standing and directed an AcuStream™ dose to theinferior conjunctiva of the test eye and a single standard drop dose tothe inferior conjunctiva/lower lid sulcus of the control eye.

Pupil diameters were measured for each patient at 30, 60, 90, 120, 150and 180 minutes after dose instillation. After the final measurement,patients underwent re-examination and fluorescein staining at the slitlamp noting any drug delivery related disruption to the corneal surface(Table 2).

TABLE 2 Measurement Schedule for Trial 1 Pre- Post- Final post-Post-instillation Type of instillation Instillation treatment slit (t =30, 60, 90, examination (Baseline) (t = 0 min) lamp exam 120 minutes)Fluorescein X X staining Slit amp eXam X X Pupillometry X X Patientvisual X analogue comfort scale

A patient Analog Visual Comfort Scale (shown below) was alsoadministered within 5 minutes of drug instillation in order to comparetheir perception of comfort associated with the two modes of topicaldelivery. Patients were asked to indicate their level of comfort duringdrug administration for each eye on the linear scale shown below andserved as the metric for later comparison.

3. Results:

a. Safety: The safety of the two delivery methods were compared by meansof a slit lamp examination (Haag-Streit 900BQ slit lamp) of the cornealsurface and anterior chamber prior to drug delivery and after the120-minute pupil diameter measurement. Fluorescein staining and bluelight illumination of the eye was similarly employed as a sensitiveindicator of epithelial integrity. No areas of epithelial damage wereobserved under slit lamp illumination or under blue light illumination.Digital images were obtained for both eyes of each patient under slitlamp illumination (FIG. 900A—Right eye, pre-dosing, AcuStream™, FIG.900B—Left eye, post-treatment, standard dropper).There was no evidenceof corneal epithelial disruption and no adverse events or complicationswere observed.b. Pupillometry:

Post-instillation pupillometry was conducted at 30-minute intervals upto three hours by a sole examiner who was blinded to the randomizationconditions. At the 90-minute time point, mean pupil diameters hadincreased from 3.34 mm to 6.95 mm for the “test” eyes and 3.35 mm to7.26 mm for control (FIG. 1000). The pupil diameter increase wasstatistically significant for both treatment conditions (Wilcoxon signedrank test p<0.005) and was sustained for 180 minutes post-instillation(see FIG. 1100).

The mean pupil diameter difference between test and control eyes atbaseline and at all post instillation time points was found to bestatistically insignificant at all time points. At the finalpost-instillation time point, there continued to be no significantdifference between test and control eyes (FIG. 1200).

c. Comfort:

Within five minutes after drug administration, patients were instructedthrough a Spanish-speaking translator and a trained ophthalmologist toplace a mark along the visual analog comfort scale indicating theirdegree of comfort for each eye. A score of 0 reflects “leastcomfortable”, while a score of 100 indicated “most comfortable”. Theline was exactly 100 mm long, enabling the generation of a numericalvalue to represent their feeling of comfort.

The average visual analog comfort scale averaged 81.7 mm for AcuStream™treated eyes versus 58.7 mm for standard drop treated eyes (refer toTable 3). Based on the average difference in scores between eyes it wasdetermined that AcuStream™ delivery was 39% more comfortable thanstandard eye drop delivery and that this difference was statisticallysignificant (Wilcoxon Signed Rank test—exact, P=0.0190).

TABLE 3 Visual Analog Comfort Scale Data Summary POPULATION TEST GROUPCONTROL GROUP N 19 19 Mean 81.7 58.7 Std Dev 24.06 36.76 Std Error 5.528.43 Median 92.0 60.0 DIFFERENCE IN POST-INSTILLATION PVACS (TEST −CONTROL), mm * N 19 Mean* 23.0 Std Dev 38.97 Std Error 8.94 Median 0.0Q1, Q3 0.0, 5.0 Min, Max −50, 100 *Calculated as the mean of individualdifferencesThe feeling of comfort or pain may be influenced by many factors. Forthe present study the factors identified included a stinging sensationelicited by the mydriatic formulation during impact of the microfluidicstream or drop. However, review of the videos obtained duringadministration revealed observable body reactions, such as forced blinkreaction, eyelids remaining closed after administration, turning thehead, shaking the head or leaning to one side. These reactions were morepronounced in the standard drop delivery group.

4. Summary

a. Method:

Twenty (20) patients were recruited for Trial 1. For each patient, drugwas administered to one eye using AcuStream™ (“test”) or standard eyedrops (“control”) and the other eye the other method. Eye selection fortreatment type was randomized and blinded. Pupil diameters at baselineand subsequent time points were measured by means of slit lampexamination and fluorescein staining prior to and after drugadministration for both delivery methods. Post-instillation pupilmeasurements were repeated at 30-minute intervals over a period of twohours by a sole examiner with no prior knowledge of the randomizationconditions.

b. Results:

There was no evidence of corneal epithelial disruption or adverse eventsassociated with either mode of administration. Mean pupil diametersincreased from 3.34 mm to 6.95 mm for the AcuStream™ treated eyes, andincreased from 3.35 mm to 7.26 mm for the standard drop delivery at 90minutes post-administration. The pupil diameter increase wasstatistically significant for both treatment conditions (Wilcoxon SignedRank test p<0.0001). The mean pupil diameter difference betweentreatment conditions was found to be statistically non-significant atall post instillation time points.

Comfort was assessed by means of an ocular comfort scale for both testand control eyes. The patient comfort score was 39% greater forAcuStream™ than for the standard eye drops. Based on video analysis, thesensation of “stinging” from the tropicamide/phenylephrine formulationwas judged to be demonstrably less for the AcuStream™ treated eyes.

D. Intraocular Pressure Reduction with Latanoprost

1. Objective:

Trial 2 compared the efficacy (dose volume equivalence) of 0.005% w/vlatanoprost for intraocular pressure reduction when delivered viaAcuStream™ (pre-trial calibration volume=9.2 μl) versus the standard eyedropper for topical drug delivery (approximate volume=30 μl).

2. Method:

a. Study Population:

Patients included in Trial 2 have previously been diagnosed with primaryopen angle glaucoma on the basis of intraocular pressure and visualfield testing, fundus examination or optical coherence tomography (OCT)data and are currently on prostaglandin analog medical therapy. Patientswith corneal abnormalities that would interfere with accurate IOPmeasurements with applanation tonometry, use of an oral or topicalophthalmic steroids within the past 14 days from screening date, anyactive ocular surface or anterior segment disease, or progressive fieldloss during the past year were excluded from the study. Thirteen men andfive women participated in the trial.

Recruited patients were taken off medical therapy for a period of 3-4weeks prior to the study to allow drug “wash out”, thereby elevatingtheir IOPs to pre-treatment levels which was confirmed by examination ofthe patients' chart history. Patients were randomly assigned as “test”(AcuStream™), or “control” (standard eye dropper). The mean age of thecontrol group and test group were 61.0 years and 65.2 years,respectively. Table 4 summarizes the patient demographics for thistrial.

TABLE 4 Patient Demographics for Trial 2 TEST CONTROL (EYE (ACUSTREAM)DROPPER) OVERALL Total N  9  9 18 Female  7 (77.8%)  6 (66.7%) 13(72.2%) Male  2 (22.2%)  3 (33.3%)  5 (27.8%) Age (Mean) 61.0 65.2 63.1Std Dev  9.90  4.47  7.76 Std Error  3.30  1.49  1.83 Median 61.0 65.064.0 Q1, Q3 56.0, 65.0 62.0, 69.0 59.0, 69.0 Min, Max 45.0, 76.0 58.0,70.0 45.0, 76.0b. Study Design:

Trial 2 was an acute prospective, randomized, actively controlled andmasked examiner design comparison of 0.005% w/v latanoprost deliveredvia AcuStream™ (pre-trial calibration volume=9.2 μl) or a standard eyedropper (approximate dose volume=30 μl) for acute IOP reduction. Thepatients assigned to either the “test” or “control” group by means of arandom numbers table in order to mitigate any potential cross-overeffects that could confound data interpretation. An odd number dictatedthat the patient was in the test group, while even-numbered patientswere in the control group.

c. Procedure:

After performing slit lamp examinations on each patient to verifyeligibility and obtaining informed consent, intraocular pressure (IOP)was measured by a sole experienced examiner who was blind to therandomized conditions. A pre-calibrated Goldmann applanation tonometercoupled to a Haag-Streit 900 EQ slit lamp was used to conduct baselineIOP measurements. Once baseline IOP data were verified to be equivalentto pre-medical therapy levels (based on patient's treatment history),the patient then continued to the dosing stage of the study.

Latanoprost solution was administered by a sole ophthalmologist to botheyes of each patient, based on the pre-determined randomized condition.As in Trial 1, patients were requested to look up slightly because theophthalmologist was standing as either an AcuStream™ dose was directedto the inferior conjunctiva or a single standard drop dose wasadministered to the inferior conjunctiva/lower lid sulcus of thepatient's eyes.

3. Results:

The average baseline IOP for the AcuStream™ group (9 patients, N=18eyes) was 18.6 mm Hg and 17.7 mm Hg for the standard dropper group (9patients, N=18 eyes). IOPs were at approximately 8 hours after dosingand decreased to 13.6 mm Hg for the test group and 13.3 mm Hg for thestandard drop group. The average decrease measured per patient was 5.0mm Hg for the test group and 4.3 mm Hg for the control group (FIG.1300). Table 5 summarizes the results:

TABLE 5 Trial 2 Results, Pre- and Post-Treatment TEST CONTROLPRE-TREATMENT IOP N 18 18 Mean 18.6 17.7 Std Dev 2.71 4.12 Std Error0.64 0.97 Median 18.0 18.0 POST-TREATMENT IOP N 18 18 Mean 13.6 13.3 StdDev 2.94 3.94 Std Error 0.69 0.93 Median 13.0 12.0 TOTAL PRESSUREREDUCTION N 18 18 Mean −5.0 −4.3 Std Dev 1.75 3.25 Std Error 0.41 0.77Median −5.0 −4.0The data were plotted graphically and revealed a large range of IOPreduction for the control group. This can be attributed to a singlepatient outlier with a measured baseline IOP (OD) of 30 mm Hg and apost-instillation IOP of 17 mm Hg. (See FIG. 1400) There was astatistically significant decrease in IOP between baseline and posttreatment measurements (Student' T-test p<0.001), and no statisticallysignificant differences in baseline IOP or IOP reduction between groups(Wilcoxon Ranked Sum test, p=0.3447).

4. Summary

a. Method: Eighteen (18) patients previously diagnosed with glaucoma andcurrently on prostaglandin analog medical therapy were identified andhad consented to participate in Trial 2. Each patient was randomizedinto either a test cohort (AcuStream™) or a control cohort (standard eyedropper), so that both eyes of a patient were treated with the samedelivery method. IOP was measured by a sole experienced examiner blindedto the randomization conditions using a pre-calibrated Goldmannapplanation tonometer.b. Results: IOP baselines were established and conformed to pre-medicaltherapy levels based on pre-study history. The average baseline IOP forthe “test” group averaged 18.6 mm Hg while the “control” group averaged17.7 mm Hg. Post-treatment IOP measurements were taken approximately 8hours after dosing, and decreased in both groups to 13.6 mm Hg for theAcuStream™ treatment group and to 13.3 mm Hg for the standard eye droptreatment group. There were no statistically significant differences inIOP reduction between groups.

E. Discussion and Conclusion

The pilot trials data reported herein demonstrate the pharmacodynamicequivalence of a 9.2 μl dose volume delivered by the AcuStream™ deviceto a 30 μl dose volume for standard eye drops (a factor of 3.3×greatervolume), for two medications: a combination formulation of tropicamide(1% w/v) and phenylephrine (2.5% w/v) for pupil dilation, andlatanoprost (0.005% w/v) formulation for intraocular pressure reduction.

Patient comfort is an important component of adherence and compliancewith prescribed medical therapies. Video analysis of patient responsesduring and immediately after drug administration and the patients'indication of comfort on the visual analog comfort scale show afavorable improvement in patient comfort when the AcuStream™ device wasused compared with standard eye drops. Slit lamp examination andfluorescein staining revealed no evidence of epithelial disruption dueto drug administration via the AcuStream™ device.

The pilot trials results demonstrate that the AcuStream™ device is asafe, effective and comfortable alternative to the use of standard eyedrop administration. The results from both trials demonstrate that theAcuStream™ device is an equally effective alternative to standard eyedrop delivery as demonstrated by comparable effects on pupil dilationand intraocular pressure, while delivering less than one-third of thevolume. Feedback from the patients also indicate that delivery withAcuStream™ is more comfortable.

Aspects, including embodiments, of the subject matter described hereinmay be beneficial alone or in combination, with one or more otheraspects or embodiments. Without limiting the description, certainnon-limiting aspects of the disclosure numbered 1-96 are provided below.As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individually numbered aspects may be used orcombined with any of the preceding or following individually numberedaspects. This is intended to provide support for all such combinationsof aspects and is not limited to combinations of aspects explicitlyprovided below:

1. A method of administering an ophthalmic agent to a topical ocularlocation of an eye of a subject, the method comprising:

-   -   delivering to the topical ocular location a dose of a liquid        formulation of the ophthalmic agent that can be wholly        incorporated into the tear film of the eye.        2. The method according to Clause 1, wherein the dose is        delivered as a stream to the topical ocular location.        3. The method according to any of Clauses 1 to 2, wherein a        known amount of ophthalmic agent is delivered to the topical        ocular location.        4. The method according to any of Clauses 1 to 3, wherein the        amount of ophthalmic agent delivered and retained on the ocular        location has a mass equal to the administered volume times the        concentration of ophthalmic agent in the liquid formulation of        the micro-dose.        5. The method according to any of the preceding clauses, wherein        the delivered dose has a volume ranging from 1 to 15 μl.        6. The method according to Clause 5, wherein the delivered dose        has a volume ranging from 3 to 10 μl.        7. The method according to any of the preceding clauses, wherein        the delivered dose is administered by a handheld device.        8. The method according to Clause 7, wherein the handheld device        comprises:    -   a container comprising the liquid formulation and an aperture;        and    -   an actuator configured to emit the delivered dose from the        container through the aperture.        9. The method according to any of the preceding clauses, wherein        the method is a method of treating the subject for an ocular        condition.        10. The method according to any of Clauses 1 to 8, wherein the        liquid formulation is preservative free.        11. A method of treating a subject for an ocular condition, the        method comprising:    -   delivering to a topical ocular location of the subject a        micro-dose of an ophthalmic agent liquid formulation effective        to treat the subject for the ocular condition.        12. The method according to Clause 11, wherein the micro-dose        has a volume ranging from 1 to 15 μl.        13. The method according to Clause 12, wherein the micro-dose        has a volume ranging 3 to 10 μl.        14. The method according to any of Clauses 11 to 13, wherein a        known amount of ophthalmic agent is delivered to the topical        ocular location.        15. The method according to any of Clauses 11 to 14, wherein the        amount of ophthalmic agent delivered and retained on the ocular        location has a mass equal to the administered volume times the        concentration of ophthalmic agent in the liquid formulation of        the micro-dose.        16. The method according to Clause 15, wherein the amount of        ophthalmic agent delivered to the topical ocular location is        determined from pulse duration and ophthalmic agent        concentration in the liquid formulation.        17. The method according to any of Clauses 11 to 16, wherein the        micro-dose is administered as a single stream.        18. The method according to Clause 17, wherein the stream is        continuous.        19. The method according to Clause 18, wherein the stream is        discontinuous.        20. The method according to any of the Clauses 11 to 16, wherein        the micro-dose is administered as a series of streams.        21. The method according to any of Clauses 11 to 16, wherein the        micro-dose is administered as a plurality of droplets.        22. The method according to any of Clauses 11 to 21, wherein the        micro-dose is self-administered.        23. The method according to any of Clauses 11 to 22, wherein the        micro-dose is administered by a handheld device.        24. The method according to Clause 23, wherein the handheld        device comprises:    -   a container comprising a liquid formulation of the ophthalmic        agent; and    -   an actuator configured to emit the micro-dose from the container        through the aperture.        25. The method according to Clause 24, wherein the container        comprises a volume of the liquid formulation sufficient to        provide multiple micro-doses.        26. The method according to any of Clauses 11 to 25, wherein the        ophthalmic agent is a cholinergic agent.        27. The method according to Clause 26, wherein the cholinergic        agent is a muscarinic agonist.        28. The method according to Clause 27, wherein the muscarinic        agonist is selected from the group consisting of: pilocarpine,        carbochol, physostigmine, methacholine and pharmaceutically        acceptable salts thereof, and combinations thereof.        29. The method according to any of Clauses 11 to 25, wherein the        ophthalmic agent is a miotic agent.        30. The method according to clause 29, wherein the ophthalmic        agent is selected from the group consisting of: pilocarpine,        carbochol, physostigmine, echothiophate, methacholine,        moxisylyte and pharmaceutically acceptable salts thereof, and        combinations thereof.        31. The method according to any of Clauses 11 to 30, wherein        ocular condition is presbyopia.        32. The method according to any of Clauses 11 to 30, wherein the        ocular condition is glaucoma.        33. The method according to Clause 32, wherein the glaucoma is        angle-closure glaucoma.        34. The method according to any of Clauses 11 to 30, wherein the        ocular condition is dry eye.        35. The method according to any of Clauses 11 to 30, wherein the        ocular condition is selected from:    -   Sjogren's Syndrome associated with ocular discomfort or dryness        or both;    -   a refractive error including hyperopia and astigmatism; and    -   post-surgical optical aberration, e.g., following cataract        surgery, keratorefractive surgery, and corneal transplantation.        36. The method according to any of Clauses 11 to 25, wherein the        active agent comprises an intraocular pressure modulatory agent.        37. The method according to Clause 36, wherein the ocular        condition is glaucoma.        38. The method according to any of Clauses 11 to 37, wherein the        liquid formulation is preservative free.        39. A method of treating a subject for presbyopia, the method        comprising:    -   delivering to a topical ocular location of the subject a        micro-dose of a miotic agent effective to treat the subject for        presbyopia without substantial adverse effects.        40. The method according to Clause 39, wherein the micro-dose        has a volume ranging from 1 to 15 μl.        41. The method according to Clause 40, wherein the micro-dosage        has a volume ranging from 3 to 10 μl.        42. The method according to any of Clauses 39 to 41, wherein the        miotic agent is selected from the group consisting of:        pilocarpine, carbochol, physostigmine, echothiophate,        methacholine, moxisylyte and pharmaceutically acceptable salts        thereof, and combinations thereof.        43. The method according to Clause 42, where the miotic agent is        pilocarpine.        44. The method according to any of Clauses 39 to 43, wherein the        miotic agent is the sole active agent in the micro-dose.        45. The method according to any of Clauses 39 to 44, wherein a        known amount of the miotic agent is delivered to the topical        ocular location.        46. The method according to any of Clauses 39 to 45, wherein the        amount of miotic agent delivered to the topical ocular location        has a mass equal to the administered volume times the        concentration of cholinergic agent in the liquid formulation of        the micro-dose.        47. The method according to Clause 46, wherein the amount of        miotic agent delivered to the topical ocular location is        determined from pulse duration and active agent concentration in        the liquid formulation.        48. The method according to any of Clauses 39 to 47, wherein the        method results in a reduction in pupil diameter ranging from        0.25 to 10 mm as compared with prior to drug administration.        49. The method according to any of Clauses 39 to 48, wherein the        method results in improvement in visual acuity ranging from 2 to        6 lines on a Jaeger or Rosenbaum near card or ETDRS Near Chart.        50. The method according to any of Clauses 39 to 49, wherein the        micro-dose is administered as a stream of the liquid        formulation.        51. The method according to Clause 50, wherein the stream is        continuous.        52. The method according to Clause 50, wherein the stream is        discontinuous.        53. The method according to any of the Clauses 39 to 49, wherein        the micro-dose is administered as a series of streams.        54. The method according to any of Clauses 39 to 49, wherein the        micro-dose is administered as a plurality of droplets.        55. The method according to any of Clauses 39 to 54, wherein the        micro-dose is self-administered.        56. The method according to any of Clauses 39 to 55, wherein the        micro-dose is administered by a handheld device that comprises:    -   a container comprising a liquid formulation of the miotic agent        and an aperture; and    -   an actuator configured to emit the micro-dose from the container        through the aperture.        57. The method according to Clause 56, wherein the container        comprises a volume of the liquid formulation sufficient to        provide multiple micro-doses.        58. The method according to any of Clauses 39 to 57, wherein the        liquid formulation is preservative-free.        59. A method of treating a subject for glaucoma, the method        comprising:    -   delivering to a topical ocular location of an eye of the subject        a dose of a liquid formulation of an intraocular pressure        modulatory agent that can be wholly incorporated into the tear        film of the eye to treat the subject for glaucoma.        60. The method according to Clause 59, wherein the delivered        dose has a volume ranging from 1 to 15 μl.        61. The method according to Clause 60, wherein the delivered        dose has a volume ranging from 3 to 10 μl.        62. The method according to any of Clauses 59 to 61, wherein the        delivered dose is administered as a stream of the liquid        formulation.        63. The method according to Clause 62, wherein the stream is        continuous.        64. The method according to Clause 62, wherein the stream is        discontinuous.        65. The method according any of Clauses 59 to 64, wherein the        topical ocular location comprises a corneal/conjunctival        location.        66. The method according to Clause 65, wherein the topical        ocular location comprises an area ranging from 2.5 to 12 μm².        67. The method according to any of Clauses 59 to 66, wherein the        delivered dose is self-administered.        68. The method according to any of Clauses 59 to 67, wherein the        delivered dose is administered by a handheld device that        comprises:    -   a container comprising the liquid formulation and an aperture;        and    -   an actuator configured to emit the delivered dosage from the        container through the aperture.        69. The method according to Clause 68, wherein the container        comprises a volume of the liquid formulation sufficient to        provide multiple delivered doses.        70. The method according to any of Clauses 59 to 69, wherein the        liquid formulation is preservative free.        71. The method according to any of Clauses 59 to 70, wherein the        intraocular pressure modulatory agent increases aqueous humor        outflow.        72. The method according to Clause 71, wherein the intraocular        pressure modulatory agent is a prostaglandin agent.        73. The method according to Clause 72, wherein the prostaglandin        active agent is latanoprost.        74. The method according to any of Clauses 59 to 73, wherein the        intraocular pressure modulatory agent decreases aqueous humor        production.        75. The method according to Clause 74, wherein the intraocular        pressure modulatory agent is a β-adrenergic receptor antagonist.        76. The method according to Clause 75, wherein the β-adrenergic        receptor antagonist is timolol.        77. The method according to any of Clauses 59 to 76, wherein the        delivered dosage has an efficacy comparable to a reference        dosage having a volume that exceeds the capacity of tear film.        78. A device configured to deliver a dose of a liquid        formulation of an ophthalmic agent to a topical ocular location        of an eye of a subject, wherein the dose is wholly accommodated        by the tear film of the eye.        79. The device according to Clause 78, wherein the dose has a        volume ranging from 1 to 15 μl.        80. The device according to Clause 79, wherein the micro-dose        has a volume ranging from 3 to 10 μl.        81. The device according to any of Clauses 78 to 80, wherein the        ophthalmic agent is a cholinergic agent.        82. The device according to any of Clauses 78 to 80, wherein the        ophthalmic agent is a miotic agent.        83. The device according to any of Clauses 78 to 80, wherein the        ophthalmic agent is an intraocular pressure modulatory agent.        84. The device according to any of Clauses 78 to 83, wherein the        device is configured to administer the dose as a stream of the        liquid formulation.        85. The device according to Clause 84, wherein the stream is        continuous.        86. The device according to Clause 84, wherein the stream is        discontinuous.        87. The device according to any of Clauses 78 to 83, wherein the        device is configured to administer the dose as a series of        streams.        88. The device according to any of Clauses 78 to 83, wherein the        device is configured to administer the dose as a plurality of        droplets.        89. The device according to any of Clauses 78 to 88, wherein the        device is a handheld device that comprises:    -   a container comprising a liquid formulation of the cholinergic        agent and an aperture; and    -   an actuator configured to emit the dose from the container        through the aperture.        90. The device according to any of Clauses 78 to 89, wherein the        liquid formulation is preservative free.        91. The device according to Clause 90, wherein the container        comprises a volume of the liquid formulation sufficient to        provide multiple delivered doses.        92. A kit comprising a device according to any of Clauses 78 to        91.        93. A kit comprising a container comprising a liquid formulation        of an ophthalmic agent, wherein the container is configured to        be operably employed in a device according to any of Clauses 78        to 91.        94. The device according to Clause 93, wherein the ophthalmic        agent is a cholinergic agent.        95. The device according to Clause 93, wherein the ophthalmic        agent is a miotic agent.        96. The device according to Clause 93, wherein the ophthalmic        agent is an intraocular pressure modulatory agent.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. Moreover, nothing disclosedherein is intended to be dedicated to the public regardless of whethersuch disclosure is explicitly recited in the claims.

The scope of the present invention, therefore, is not intended to belimited to the exemplary embodiments shown and described herein. Rather,the scope and spirit of present invention is embodied by the appendedclaims. In the claims, 35 U.S.C. § 112(f) or 35 U.S.C. § 112(6) isexpressly defined as being invoked for a limitation in the claim onlywhen the exact phrase “means for” or the exact phrase “step for” isrecited at the beginning of such limitation in the claim; if such exactphrase is not used in a limitation in the claim, then 35 U.S.C. § 112(f) or 35 U.S.C. § 112(6) is not invoked.

What is claimed is:
 1. A method of treating a subject for glaucoma, themethod comprising: administering to a topical ocular location of thesubject a micro-dose a precise, known mass of an intraocular pressuremodulatory agent effective to treat the subject for glaucoma, whereinthe micro-dose is administered by a handheld device that comprises: acontainer comprising a liquid formulation of the intraocular pressuremodulatory agent and a single aperture; and an actuator configured toemit the micro-dose from the container through the single aperture. 2.The method according to claim 1, wherein the micro-dose has a volumeranging from 1 to 15 μl.
 3. The method according to claim 2, wherein themicro-dose has a volume ranging from 3 to 10 μl.
 4. The method accordingto claim 1, wherein the intraocular pressure modulatory agent increasesaqueous humor outflow.
 5. The method according to claim 1, wherein theintraocular pressure modulatory agent is a prostaglandin agent.
 6. Themethod according to claim 1, wherein the prostaglandin active agent isselected from the group consisting of latanoprost, bimatoprost,travoprost, and tafluprost.
 7. The method according to claim 1, whereinthe intraocular pressure modulatory agent decreases aqueous humorproduction.
 8. The method according to claim 7, wherein the intraocularpressure modulatory agent is a beta blocker.
 9. The method according toclaim 8, wherein the beta blocker antagonist is selected from the groupconsisting of timolol, betaxolol, levobunolol and atenolol.
 10. Themethod according to claim 7, wherein the intraocular pressure modulatoryagent is a carbonic anhydrase inhibitor.
 11. The method according toclaim 10, wherein the carbonic anhydrase inhibitor is selected from thegroup consisting of: acetazolamide, dorzolamide, brinzolamide,methazolamide, dichlorphenamide and diamox.
 12. The method according toclaim 1, wherein the intraocular pressure modulatory agent bothdecreases ocular fluid production and increases ocular fluid drainage.13. The method according to claim 12, wherein the intraocular pressuremodulatory agent is an alpha agonist.
 14. The method according to claim13, wherein the alpha agonist is selected from the group consisting ofapraclonidine or brimonidine.
 15. The method according to claim 1,wherein the intraocular pressure modulatory agent increases fluiddrainage.
 16. The method according to claim 15, wherein the intraocularpressure modulatory agent is a rho kinase inhibitor.
 17. The methodaccording to claim 16, wherein the rho kinase inhibitor is netarsudil.18. The method according to claim 1, wherein the micro-dose comprises acombination of two or more active agents.
 19. The method according toclaim 18, wherein the combination of two or more active agents isselected from the group of combinations consisting of: a beta blockerand a carbonic anhydrase inhibitor, an alpha agonist and a beta blocker;and a carbonic anhydrase inhibitor and an alpha agonist.
 20. The methodaccording to claim 1, wherein the intraocular pressure modulatory agentis the sole active agent in the micro-dose.
 21. The method according toclaim 1, wherein the precise, known mass of intraocular pressuremodulatory agent delivered to the topical ocular location has a massequal to the administered volume times the concentration of intraocularpressure modulatory agent in the liquid formulation of the micro-dose.22. The method according to claim 21, wherein the precise, known mass ofintraocular pressure modulatory agent delivered to the topical ocularlocation is determined from pulse duration and active agentconcentration in the liquid formulation.
 23. The method according toclaim 1, wherein the micro-dose is administered as a collimated streamof the liquid formulation.
 24. The method according to claim 23, whereinthe collimated stream is continuous.
 25. The method according to claim23, wherein the collimated stream is discontinuous.
 26. The methodaccording to claim 1, wherein the micro-dose is administered as a seriesof streams.
 27. The method according to claim 1, wherein the micro-doseis administered as a plurality of droplets.
 28. The method according toclaim 1, wherein the micro-dose is self-administered.
 29. The methodaccording to claim 1, wherein the container comprises a volume of theliquid formulation sufficient to provide multiple micro-doses.
 30. Themethod according to claim 1, wherein the liquid formulation ispreservative-free.
 31. The method according to claim 1, wherein thedevice comprises an image-based alignment system configured to enableself-alignment by the user of the aperture with the target location. 32.The method according to claim 31, wherein the subject employs theimage-based alignment system to align the aperture with the targetlocation.